Annals of Oncology Advance Access originally published online on October 9, 2006
Annals of Oncology 2007 18(1):45-51; doi:10.1093/annonc/mdl334
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© 2006 European Society for Medical Oncology
breast cancer |
Late risk of relapse and mortality among postmenopausal women with estrogen responsive early breast cancer after 5 years of tamoxifen
1 Division of Medical Oncology, British Columbia (BC) Cancer Agency
2 Department of Medicine, University of British Columbia, Vancouver, BC
3 Breast Cancer Outcomes Unit
4 Population and Preventive Oncology Programs
5 Victoria
6 Fraser Valley, BC Cancer Agency, Canada
* Correspondence to: Dr H. Kennecke, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, Canada V5Z 4E6. Tel: +1 604 877 6000, ext 2707; E-mail: hkenneck{at}bccancer.bc.ca
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Abstract |
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Background: Letrozole after 5 years of adjuvant tamoxifen results in a significant reduction in risk of recurrence from estrogen receptor (ER) positive breast cancer. An individualized estimate of the risk of relapse and death after 5 years of tamoxifen could improve decisions regarding extended hormonal therapy.
Methods: The British Columbia Breast Cancer Outcomes database was used to identify women aged 45 years or older at the time of diagnosis with early-stage (I–IIIA) breast cancer who received tamoxifen and were disease free 5 years after diagnosis. Ten-year breast cancer event rates and mortality were calculated as well as annualized hazard rates of recurrence.
Results: A total of 1086 women were identified with a median age of 64 years and follow-up of 10.5 years. The relative risk (RR) of death was 3.1 (P = 0.003) and for recurrence was 1.7 (P = 0.037) for N1 (one to three positive nodes) versus N0 (zero nodes positive) disease. N2 (four to nine nodes positive) had a RR of 5.8 (P < 0.001) for death and 3.0 (P = 0.002) for recurrence. Low tumor grade and high ER level subgroups had a more favorable prognosis. Annual breast cancer risk between years 6 and 10 was, respectively, 2.2%, 3.5% and 7.6% for N0, N1 and N2 disease and 2.6% and 4.5% for T1 and T2 breast cancer.
Conclusion: T and N stages predicted late relapse and death from breast cancer in a population-based cohort of postmenopausal women. Risk estimates reported herein may be used to optimize decision making regarding adjuvant therapy after 5 years of tamoxifen.
Key words: breast cancer, estrogen receptor, mortality, relapse, risk, tamoxifen
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introduction |
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Over half of the 15-year relapses and mortality from breast cancer occur >5 years from diagnosis [1, 2]. Results of the ATLAS and aTTOM trials are pending and at this time, >5 years of tamoxifen is not recommended following the results from NSABP B-14 and other trials which have been interpreted as consistent with laboratory findings that the agonist activity of tamoxifen becomes dominant with time and may promote tumor growth [3–5]. Studies of raloxifene would indicate that this agent may have similar potential to promote estrogen-dependent growth [6, 7] and therefore long-term use of raloxifene or its use after 5 years of tamoxifen is not currently recommended without clinical data showing safety and efficacy.
Aromatase inhibitors (AIs) have a different mechanism of action than tamoxifen or raloxifene and result in a profound reduction in serum estradiol levels in postmenopausal women. In the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA-17 trial, switching from tamoxifen to the AI letrozole after 5 years of tamoxifen improved disease-free survival [hazard ratio (HR) = 0.58, P < 0.001] with a median follow-up of 30 months [8]. In the node-positive subset, an overall survival benefit was observed (HR = 0.61, P = 0.040) [9]. The HR reductions are impressive but they are the absolute gains from an AI that women must weigh against the risks of therapy. AIs have side effects including musculoskeletal symptoms, hot flushes and an increased risk of osteoporotic fracture [8–14].
Three third generation AIs have been compared with 5 years of tamoxifen, either given upfront for 5 years [10–12], after 2–3 years of tamoxifen [13, 14] or after 5 years of tamoxifen [8, 9]. All three strategies were supported in a recent American Society of Clinical Oncology technology assessment report [15].
A practical clinical question is which patients are at greatest risk of recurrence after 5 years of tamoxifen and thus would potentially benefit from extended adjuvant hormonal therapy. This report describes the risk of a breast cancer event and mortality during years 6–10 after diagnosis in postmenopausal women with early-stage breast cancer who were event free after 5 years of tamoxifen in a large, population-based cohort treated in British Columbia (BC), Canada.
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methods |
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Women diagnosed with breast cancer in BC between 1989 and 1994, who were of age 45 years and older and referred to the British Columbia Cancer Agency (BCCA) were included. Approximately 75% of women diagnosed with breast cancer in BC were referred to the BCCA during this period. The age limit was selected to ensure that all patients would be aged 50 years or older after completing 5 years of tamoxifen and would be likely to be postmenopausal and therefore potentially eligible for AI therapy. To ensure complete mortality reporting, outcome data after 31 December 2003, were censored. Other inclusion criteria were estrogen receptor (ER) positive or unknown and stage I, II or IIIA breast cancer (T1–3; N0–3a; M0) [16]. Subjects with documented ER negative breast cancer were excluded. Subjects were excluded if they had a prior or synchronous contralateral breast cancer, locally advanced (including T3, N1/2) or metastatic disease at diagnosis.
Pathology characteristics abstracted included nodal status and number of positive axillary nodes, tumor size, grade, ER status and the presence of lymphatic or vascular invasion in the primary site. ER status was determined either by dextran-coated charcoal (DCC) assay or by immunohistochemical staining.
Immunohistochemical staining of the ER was graded according to the following scale: ER 0, <10% of cells staining positive (corresponding Allred score 0–2); ER 1+, 10%–20% cells staining weakly positive (Allred score 3, 4); ER 2+, 20%–60% of cells staining moderately positive (Allred score 5, 6); ER3+, 60%–100% staining strongly positive (Allred score 7, 8). Tumors were considered highly ER positive if they were scored ‘ER 3+’ on immunohistochemistry or >100 fmol/mg on DCC assay. ‘ER1+’ or ‘ER2+’ tumors or those <100 fmol/mg on DCC assay were classified low/moderate ER positive. The majority of patients had a pathology review on referral to the BCCA and if done, the review diagnosis was used to describe pathologic characteristics.
Patients were treated with definitive surgery and adjuvant radiation and systemic therapy as described in BCCA cancer management guidelines which evolved over time [17]. Patients were included only if there was documentation in the BCCA Provincial Pharmacy Database that they received a tamoxifen prescription within 1 year of diagnosis and another prescription between 3 and 6 years after diagnosis. A cutoff point of 6 years was chosen in order to capture patients who started tamoxifen late due to treatment with adjuvant chemotherapy. None of the women in the study cohort had an event, defined as a local, regional or distant relapse, or a new contralateral breast primary, within the first 5 years from their primary diagnosis.
The primary end points were breast cancer event rate and breast cancer-specific mortality during the interval from 5 to 10 years after diagnosis. A breast cancer event was defined as a local (breast or chest wall), regional (ipsilateral axillary, infraclavicular, internal mammary or supraclavicular) or distant recurrence, a new contralateral breast cancer or death from breast cancer before a recorded relapse. A local or regional event occurring within 30 days of a distant event was scored as a distant event. Breast cancer-specific mortality was defined as death where breast cancer was the primary or underlying cause of death.
Univariate and multivariable analyses were carried out to assess the relationship between outcome and predetermined patient, tumor and treatment characteristics. In the multivariable analyses, cases with unknown values in any of the covariates were excluded. Relative Risks (RRs) were estimated for each variable on the 10th anniversary of diagnosis.
Annual hazard of recurrence was defined as the fraction of patients who recurred during a 1-year interval. Annual hazard rates estimating the risk of occurrence of a breast cancer event were calculated for the T1, T2, N0, N1 and N2 cohorts. Kaplan–Meier survival curves for tumor grade and ER level were calculated and compared with pairwise log-rank tests. All statistical analyses were carried out with SPSS (v 13.0) software (SPSS Inc., Chicago, IL).
The study was approved by the Research Ethics Board of the BCCA, University of BC.
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results |
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Among 12 974 patients diagnosed with invasive breast cancer in BC during 1989–1994, 1086 met eligibility criteria and formed the study group (Table 1). The median follow-up time after initial diagnosis was 10.5 years. The median age was 64 years. Ductal histology represented 89% of the cases. There were 83% with ER positive disease and 17% were ER unknown. Local therapy was breast conserving surgery (BCS) and adjuvant radiation (51%), mastectomy alone (30%), mastectomy followed by radiation (13%) and BCS alone (6%). The majority was either axillary node positive (53%) or node negative (42%). The median number of nodes removed was 10 and only 12% had fewer than six nodes removed. All patients received tamoxifen, with 22% receiving chemotherapy before the initiation of tamoxifen.
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type and relative frequency of breast cancer events
Table 2 shows the number and relative frequency of first breast cancer events. A total of 159 patients (15%) developed a breast cancer event by the 10th year. Approximately one half of the events were distant relapses (53%) and approximately one-fifth were either a contralateral breast cancer (21%) or a locoregional recurrence (17%).
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risk factors for recurrence
Table 3 shows the 10-year results of the multivariate analysis of factors associated with breast cancer mortality and breast cancer events. Only initial T stage and initial N stage were statistically significant predictors of both death and a breast cancer event at 10 years from diagnosis. Patients with one to three positive nodes had a RR of 3.1 [95% confidence interval (CI) 1.47 to 6.59; P = 0.003] for death and 1.7 (95% CI 1.03 to 2.90; P = 0.037) for a breast cancer event compared with patients with node-negative breast cancer. Patients with four to nine pathologically involved nodes had a 5.8 (95% CI 2.30 to 14.71; P < 0.001) RR for death and a RR of 3.0 (95% CI 1.50 to 6.12; P = 0.002) for developing a breast cancer event compared with patients with node-negative breast cancer. The RR of a T2 compared with a T1 tumor was 2.7 (95% CI 1.49 to 5.20; P = 0.001) for death and 1.6 (95% CI 1.00 to 2.55; P = 0.049) for a breast cancer event at 10 years from diagnosis.
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Low-grade tumors had a more favorable event free survival (EFS) than grade 2 tumors, with borderline statistical significance (Table 3). The grade 1 subgroup was small, limiting the power of the analysis. High ER positive breast cancer was associated with a significantly reduced breast cancer event risk (RR = 0.52) but not mortality compared with ER low/moderate breast cancer. Other prognostic factors including lymphovascular invasion status and the use of chemotherapy did not significantly affect outcomes at 10 years from diagnosis. In univariate analysis (data not shown) age, histological subtype and number of nodes removed were not predictive of breast cancer event risk; so these variables were not included in the multivariate analysis.
Kaplan–Meier analyses illustrate the effect of tumor grade (Figure 1) and level of ER expression (Figure 2) on EFS. Log-rank comparisons indicate a continuing risk of events for grades 2 and 3 tumors between years 6 and 10 in comparison to grade 1 tumors which exhibited a plateau in risk which remained very low (6.1%) at 10 years from diagnosis. Both high ER level and low/moderate ER level tumors demonstrated an ongoing risk of events with a more favorable prognosis for ER high tumors (Figure 2).
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mortality and event rates
Table 4 shows actual rates of breast cancer mortality and events at 10 years from diagnosis. The risk of a breast cancer event was 10.4%, 15.9% and 32.1% for patients with pathologically negative, N1 and N2 disease, respectively. These rates were paralleled by breast cancer-specific mortality that varied between one-third and two-thirds of the breast cancer event rates.
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The annual hazard of a breast cancer event was calculated for N stage and T stage (Figures 3 and 4). Hazard rates for patients with four to nine positive nodes were variable due to the small size of the cohort. The annual HRs of a breast cancer event gradually declined between the fifth and 13th year after diagnosis. During years 6–10, the average annual hazards of a breast cancer event were 2.2%, 3.5% and 7.6% for the N0, N1 and N2 cohorts, respectively. During the same time period, the average annual hazard of a breast cancer event was 2.6% for T1 and 4.5% for T2 tumors. The hazard rates for all subgroups continued to be greater than zero by year 13 from diagnosis.
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The effect of tumor grade on breast cancer-specific mortality (Table 5) and breast cancer event rate (Table 6) was determined for the node-negative cohorts. In the grade 1 subset, patients with T1 and T2 tumors had no deaths and a very low event rate (3.6%) at 10 years from diagnosis. Overall, grade 2 and grade 3 node-negative tumors had similar outcomes but small sample size resulted in variance between the groups.
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discussion |
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The purpose of this analysis was to describe the natural history of early-stage, ER responsive breast cancer among postmenopausal women who were event free after completing 5 years of tamoxifen. Overall, 15% of patients developed a breast cancer event during years 6–10 after diagnosis, of which approximately half (53%) were distant metastases. Similar outcomes were observed in the placebo group of the MA-17 study. In that study, overall 13% of patients experienced a breast cancer event of which 57% were distant relapses, 23% were locoregional recurrences and 20% were contralateral breast cancers [8].
The current study shows that standard pathologic factors of risk continue to be prognostic during the second 5 years after tamoxifen with initial tumor stage and biology continuing to influence events even 10 years after diagnosis and therapy with tamoxifen. Recent reports of the molecular portrait of recurrent tumors support this observation and indicate a remarkable similarity between the initial tumor and the recurrence [18]. Results of NCIC MA-17 indicate that a proportion of tumors remain sensitive to adjuvant hormonal therapy with letrozole after 5 years of tamoxifen.
Of the clinical and pathologic factors evaluated in multivariate analysis, initial tumor size and nodal status were the only variables that influenced both breast cancer mortality and event rates. A previous report in a less homogeneous cohort of patients enrolled on seven Eastern Cooperative Oncology Group trials of adjuvant systemic therapy showed similar results [1]. Patients with greater nodal involvement had a higher peak hazard of recurrence in years 0–5 and a higher frequency of recurrence beyond 5 years from diagnosis. ER-positive patients experienced a relatively constant annual hazard of recurrence in years 5–8 compared with years 8–12 (5.2% versus 4.6%, respectively). Data were not presented according to nodal status in the ER-positive subgroup. In the current study, we have clearly defined the nodal cohorts allowing individualized estimation of risk. The estimated annual hazard rate of a breast cancer event during years 6–10 after diagnosis was 2.2%, 3.5% and 7.6% for the N0, N1 and N2 cohorts, respectively.
In the current study, high ER positive status was associated with an 
50% lowering in the risk of a breast cancer event at 10 years compared with patients with low/moderate ER tumors. However, this difference did not impact on mortality. In the Early Breast Cancer Trialists' Collaborative Group report [19], the benefit of tamoxifen was directly related to the degree of ER expression. Five years of adjuvant tamoxifen led to a 49% and 45% reduction in recurrence and mortality, respectively, in women whose primary tumor was ER >100 fmol/mg. The respective benefits were only 36% and 27% in those with ER 10–100 fmol/mg [19]. There has been a renewed interest in defining a spectrum of hormone response [20] and molecular predictive factors of hormone responsiveness [21, 22] which were not available to study in this cohort at the time of analysis. The value of ER, progesterone receptor, epidermal growth factor receptors and HER2 as a predictor of response to early adjuvant therapy with tamoxifen has been recently evaluated by Dowsett et al. [23]. In this report, HER2 positive cancers did not benefit significantly from adjuvant tamoxifen. The use of predictive molecular markers other than ER after 5 years of adjuvant tamoxifen remains to be determined.
Tumor grade was not found to be an independent predictor of outcome but a trend was seen with grade 1 having the lowest and grade 3 tumors having the highest risk of recurrence. A previous study reported the 10-year natural history of node-negative, tamoxifen-untreated, ER-positive and -negative breast cancer [24]. Tumor size and grade were significant predictors of risk and patients with T1, grade 1 tumors had a more favorable prognosis and a plateau in risk after 5 years. In our study, patients with low-grade, node-negative tumors had a <5% risk of a breast cancer event and a 0% risk of breast cancer death after 5 years of tamoxifen. Such patients may have been underrepresented in the current study as they did not routinely receive adjuvant tamoxifen according to the BCCA provincial adjuvant guidelines during 1989–1994 [25]. A further study [26] found a paradoxically increased risk of recurrence among grade 2 tumors compared with grade 3 tumors during the second 5 years after tamoxifen. This phenomenon was not observed in our cohort, which was larger.
We deliberately defined our primary end point breast cancer event rate, to be similar to the ‘disease-free survival’ end point used in the recent major adjuvant trials of AIs [8–14]. This allows estimation of absolute benefit by application of the trial HRs to the estimated risks in our study. The risk of a breast cancer event in the second 5 years after diagnosis increased from 10% for patients with node-negative disease to 16% for patients with one to three positive nodes and 32% for patients with four to nine positive nodes (P < 0.001). If extended adjuvant therapy reduced the event rate by 40%, the absolute reduction in risk of an event would be 4%, 6% and 13% for patients with zero, one to three or four to nine involved nodes, respectively. T stage was independently prognostic and patients with T2 tumors had an event rate of 20% and would experience a potential absolute reduction in breast cancer event risk of 8%. In part, due to the inclusion of often curable contralateral breast cancers and locoregional recurrences in the breast cancer event rate, a women's risk of dying of breast cancer was generally only one half to two-thirds of her risk of a breast cancer event. This discrepancy between rates should be considered when making recommendations regarding extended adjuvant therapy.
Our results indicate that in a population-based setting, subgroups of women may be identified who are at variable levels of risk of relapse after 5 years of tamoxifen. Standard pathologic prognostic markers may be used to stratify as patients at high, intermediate and low risk of breast cancer relapse and death. Node-positive or T2 tumors are associated with a relatively high risk (>15%) of relapse or second breast cancer. Women with initially node-negative and grade 2 or 3 tumors are at intermediate risk of relapse of 10%. A small subset of postmenopausal women can be identified who are at low (<5%) risk of relapse and may be adequately treated by 5 years of tamoxifen. The subgroup analysis of node-negative patients should be approached cautiously due to small number of patients and should be further investigated in other databases. For women whose adjuvant therapy included an AI during the first 5 years after diagnosis, the risk of breast cancer as well as the role for further adjuvant hormonal therapy is not yet defined and will be determined by the results of randomized clinical trials and population-based studies.
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Presented in part at the 27th Annual San Antonio Breast Cancer Conference, 8–11 December 2004.
Received for publication March 28, 2006. Revision received July 15, 2006. Accepted for publication August 14, 2006.
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