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Prognostic factors of early distant recurrence in hormone receptor-positive, postmenopausal breast cancer patients receiving adjuvant tamoxifen therapy
Results of a retrospective analysis
Article first published online: 20 APR 2007
Copyright © 2007 American Cancer Society
Volume 109, Issue 11, pages 2197–2204, 1 June 2007
How to Cite
Debled, M., MacGrogan, G., Brouste, V., Mathoulin-Pelissier, S., Durand, M. and Mauriac, L. (2007), Prognostic factors of early distant recurrence in hormone receptor-positive, postmenopausal breast cancer patients receiving adjuvant tamoxifen therapy. Cancer, 109: 2197–2204. doi: 10.1002/cncr.22667
- Issue published online: 18 MAY 2007
- Article first published online: 20 APR 2007
- Manuscript Accepted: 19 JAN 2007
- Manuscript Revised: 16 JAN 2007
- Manuscript Received: 5 DEC 2006
- Pfizer, France
- breast cancer;
- aromatase inhibitors;
- early recurrences;
- prognostic factors
Current adjuvant hormone therapy in postmenopausal women with breast cancer is debatable between upfront aromatase inhibitors (AIs) and sequential treatment with tamoxifen. A major concern is the higher rate of early recurrences observed with sequential treatment. The authors conducted a retrospective analysis to identify risk factors of early recurrences in hormone receptor (HR)-positive, postmenopausal women within the first 3 years of adjuvant tamoxifen.
Between 1986 and 2000, operable breast cancer patients who received exclusively adjuvant tamoxifen for at least 3 years were selected from the authors' institutional database. Age, histology, pathologic tumor size, modified Scarff-Bloom-Richardson (mSBR) grade, mitotic index, tumor necrosis, peritumoral vascular emboli (PVE), HR status, and the number of involved axillary lymph-node were considered as prognostic factors of recurrence.
Among 715 patients who met the inclusion criteria, a distant recurrence occurred in 38 patients (5.3%) within the first 3 years of tamoxifen therapy. Significant prognostic factors of early recurrence were mSBR, axillary lymph node involvement, tumor necrosis, mitotic index, PVE, and pathologic tumor size. Grade 1 and/or lymph node-negative tumors were excluded from the multivariate analysis (1 recurrence in 208 patients). In this model, mSBR grade 3 was the only significant predictive factor of early recurrence (hazard ratio, 3.72; P < .001).
In this study, a subset of patients was identified that was at low-risk of early recurrence (mSBR grade 1 and/or negative lymph node status). Women in that subset could be treated using sequential hormone therapy with tamoxifen and AIs. In women with mSBR grade 3 or lymph node-positive tumors, an upfront treatment with AIs seemed to be the current optimal strategy. Cancer 2007. © 2007 American Cancer Society.
Tamoxifen-based endocrine therapy long has been the standard adjuvant treatment for patients with hormone receptor (HR)-positive breast cancer. In the adjuvant setting, the pivotal role of tamoxifen has been established in successive overviews by the Early Breast Cancer Trialists' Collaborative Group. A 5-year tamoxifen treatment reduces the annual breast cancer recurrence and death rates by 41% and 33%, respectively.1
The introduction in the 1990s of third-generation aromatase inhibitors (AIs) (anastrozole, exemestane, and letrozole) challenged the position of tamoxifen. AIs demonstrated a similar or superior activity compared with megestrol acetate as second-line therapy for advanced breast cancer after tamoxifen failure.2–5 The direct comparison of AIs with tamoxifen as first-line hormone therapy for advanced breast cancer resulted in equivalent efficacy or a significant benefit in favor of AIs.6–9 These results have led to the evaluation of AIs in the adjuvant setting according to 3 different strategies: an upfront comparison with tamoxifen for 5 years,10, 11 a 5-year sequential treatment starting with 2 or 3 years of tamoxifen followed by 2 or 3 years of AI,12, 13 and an extended treatment with AIs after 5 years of tamoxifen.14 Irrespective of the treatment sequence, results from randomized phase III trials displayed significant and constant improvements in disease-free survival (DFS) with AI adjuvant endocrine therapy.10–14 Widely disseminated treatment guidelines now incorporate AIs into the adjuvant treatment of postmenopausal women with estrogen receptor (ER)-positive breast cancer.15
A side-by-side comparison of these trials must be interpreted cautiously, because inclusion criteria and definitions of primary endpoints differed. However, it appears that the 5-year sequential treatment may provide a higher reduction in the risk of recurrence (27%–41%) than a 5-year treatment with AI alone (17%–19%).10–13 The sequential strategy also could reduce the risk of cumulative toxicities. However, according to Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group 1–98 (BIG 1–98) trials, the sequential strategy of using upfront tamoxifen resulted in a higher risk of early recurrence, whereas absolute differences of 1.7% and 2.5%, respectively, were observed in favor of AIs after 3 years of follow-up.10, 11 To identify patients who were eligible for sequential endocrine therapy, we performed a monocentric, retrospective analysis to identify risk factors of early recurrences among postmenopausal women within the first 3 years of adjuvant tamoxifen therapy.
MATERIALS AND METHODS
Between 1986 and 2000, 4987 consecutive patients with nonmetastatic, operable breast cancer were entered onto our database. Postmenopausal, HR-positive (ER-positive and/or progesterone receptor [PgR]-positive) women with operable breast cancer who underwent surgery in our institution (Institut Bergonie, Bordeaux, France) without receiving previous neoadjuvant treatments were eligible for the analysis. These patients had to receive adjuvant tamoxifen for at least 3 years in the absence of disease recurrence. Exclusion criteria included a previous history of breast carcinoma, concurrent contralateral breast cancer, pathologic data missing, premenopausal status, negative or undetermined HR status, and no tamoxifen therapy. Patients who were followed for <3 years and did not develop distant recurrences were excluded from the analysis. Patients who had received chemoendocrine therapy were excluded because of the small number of patients involved (n = 27). Follow-up was performed according to the European Good Clinical Practice requirements and consisted of regular physical examinations, an annual x-ray mammogram, and additional assessments in case of suspected metastases.
Definition of Prognostic Factors
Age, histology, pathologic tumor size, histoprognostic tumor grade, mitotic index, tumor necrosis, peritumoral vascular emboli (PVE), ER/PR status, and the number of involved axillary lymph nodes were considered as possible prognostic factors of recurrence. Clinical and pathologic characteristics were analyzed according to the hospital-recorded file at the time of treatment initiation. Pathologic tumor size was measured on fresh surgical specimens. A modified version of the Scarff-Bloom-Richardson (mSBR) grading system was used. Mitotic index was calculated as a function of the number of observed mitoses in 10 consecutive high-power fields (×400): A score of 1 was associated with <5 mitoses, a score 2 indicated from 5 to 15 mitoses, and a score 3 indicated >15 mitoses. Tumor necrosis was coded according to the presence or absence of necrosis. PVE were defined as the presence of neoplastic emboli within unequivocal vascular lymphatic or capillary lumina in areas adjacent to the breast tumor. The vascular structures involved (lymphatic vessels or veins) were not specified.16 ER status and PgR status were determined by a radioligand assay with cut-off values of 10 fmol/mg and 15 fmol/mg proteins, respectively. There was a mean number of 15 lymph nodes per axillary dissection. Each lymph node was cut into 2-mm-thick slices, and the entire lymph node was submitted for pathologic analysis.17
An additional exploratory immunohistochemical analysis was performed on a tissue microarray (TMA) to control for HR status and to detect the expression of biologic factors that potentially implicated tamoxifen resistance. Hollande-fixed, paraffin-embedded tumor blocks were obtained from the primary breast tumors of women who presented with distant recurrences during the first 3 years of adjuvant tamoxifen. Clearly defined tumor areas were selected and, 4 tissue cores, which measured 0.6 mm in greatest dimension, were obtained from each donor block and mounted onto a recipient block using a TMA instrument according to the manufacturer's instructions (Alphelys, France). Four-micrometer TMA sections were deparaffinized, rehydrated, and treated in a pressure cooker for 20 minutes in a 0.01-M citrate buffer, pH 6.0, before processing in an automatic immunohistochemistry staining machine according to standard procedures (TechMate 500; DakoCytomation, Trappes, France). Tissue sections were incubated for 60 minutes with HER2 antibody (DA485; DakoCytomation; 1/2000 dilution), vascular endothelial growth factor receptor 2 (VEGF-R2) antibody (sc-6251; Santa Cruz Biotechnology, Santa Cruz, Calif; 1/1000 dilution),18 ER antibody (1D5; DakoCytomation; 1/100 dilution), and PgR antibody (PgR636; DakoCytomation; 1/100 dilution). Staining for epidermal growth factor receptor (EGFR) was performed using the EGFR PharmDx kit according to the manufacturer's instructions (DakoCytomation).
HER2 and EGFR expression levels were evaluated semiquantitatively according to a standard protocol (Herceptest; DakoCytomation). ER and PgR expression levels were evaluated semiquantitatively with cut-off values of 10% positive invasive tumor cells. VEGF-R2 expression was evaluated as described previously.18 Briefly, the intensity of VEGF-R2 cytoplasmic staining was evaluated semiquantitatively using a classification from 0 to 3+ to indicate lack of staining (0), low staining intensity (1+), intermediate staining intensity (2+), and high staining intensity (3+).
All inclusion and exclusion criteria and selected prognostic factors were defined prospectively before the analysis began. Endpoints were planned according to usual published analyses. The events analyzed consisted of supraclavicular or distant recurrences of breast cancer that occurred within 3 years after the initiation of adjuvant tamoxifen. All events reported beyond that period were censored. Event-free survival (EFS) rates were calculated by using the Kaplan-Meier method. The significance of each prognostic factor was computed using a log-rank test, and the test was considered statistically significant when the P value was ≤.05. A multivariate analysis (Cox proportional-hazards model) was adjusted for predefined prognostic factors. Prognostic factors that were entered onto the multivariate model had to reach the statistical significance level of ≤.05 in the univariate analysis. This analysis was conducted according to the Reporting Recommendations for Tumor Marker guidelines for prognostic studies reported by the Statistics Subcommittee of the National Cancer Institute-European Organization for Research and Treatment of Cancer Working Group on Cancer Diagnostics.19
Patient and Treatment Characteristics
According to the criteria for inclusion and exclusion, 715 patients were selected from the 4987 women who were entered into our database. The reasons for exclusion from the analysis included a history of breast carcinoma or concurrent contralateral breast cancer (n = 499 women), pathologic data missing (n = 370 women), premenopausal status (n = 1257 women), negative or undetermined HR status (n = 1040 women), no tamoxifen treatment (n = 1030 women), adjuvant chemotherapy (n = 27 women), and death without recurrence or <3 years of follow-up (n = 49 women). The main clinical and pathologic characteristics of assessable patients are summarized in Table 1. Among the selected patients, 154 patients (21.5%) did not receive radiation therapy.
|Characteristic||No. of patients||%|
|Median age at diagnosis (range), y||64 (43–88)|
|Pathologic tumor size, mm|
|Unknown or not feasible||61||8.5|
|Peritumoral vascular emboli|
|Axillary lymph node involvement|
Recurrence and Analysis of Prognostic Factors
During the first 3 years of tamoxifen therapy, 38 patients developed a distant recurrence (5.3%). The 3-year EFS rate was 94.7%. The distribution of events over the time is shown in Table 2.
|Period, mo||No. of exposed patients||Distant recurrence|
|No. of patients||%|
In the univariate analysis, significant prognostic factors of early recurrence were mSBR grade, axillary lymph node involvement, tumor necrosis, mitotic index, PVE, and pathologic tumor size (Table 3). Although the likelihood was not significant, patients with negative PgR status were more likely to develop a recurrence (7.2% vs 4.1%; P = .068). Neither age nor histology was associated significantly with early recurrences. Because there was only 1 recurrence among the 155 patients who had negative lymph node status and only 1 recurrence among the 169 patients who had mSBR grade 1 tumors, these subsets of patients were not suitable for the Cox regression model. The multivariate analysis included patients who presented with lymph node-positive and mSBR grade 2 or 3 ductal carcinomas; thus, mSBR grade, tumor necrosis, mitotic index, PVE, and pathologic tumor size were selected as prognostic factors. In this model, mSBR grade 3 was the only significant predictive factor of early recurrence during the first 3 years of tamoxifen therapy (hazard ratio, 3.72; 95% confidence interval, 1.79–7.73; P < .001). Approximately 16% of mSBR grade 3, lymph node-positive patients developed recurrent disease within the first 3 years of tamoxifen therapy (Table 4). Three of 55 patients (5.4%) who had lobular carcinoma developed an early recurrence.
|Prognostic factor||No. of patients||No. of events (%)||P|
|Lymph node status|
|Pathologic tumor size, mm|
|Lymph node status||No. of early recurrences/no. of patients (%)|
|mSBR 1||mSBR 2||mSBR 3||Total|
|Negative||0/44 (0)||0/64 (0)||0/29 (0)||0/137 (0)|
|Positive||1/119 (0.8)||13/265 (4.9)||18/115 (15.6)||32/499 (6.4)|
|Total||1/163 (0.6)||13/329 (3.9)||18/144 (12.5)||32/636 (5)|
Results from additional biologic analyses of tumors that subsequently recurred are presented in Table 5. Among the patients who were considered biochemically HR-positive (for ER and/or PgR), 3 of 38 patients (7.9%) with recurrent disease were identified as HR-negative (for ER and PgR) using an immunohistochemical technique (the 1D5 antibody for ER and the PgR636 antibody for PgR). Five patients (13.2%) overexpressed HER2 (3+), and 1 additional patient expressed HER2 with 2+ positivity. The majority of patients (89.4%) with recurrent disease did not express EGFR, whereas no correlation was demonstrated for the expression of VEGF-R2.
|Group||No. of tumors||%|
|Hormone receptor status|
In this retrospective analysis, distant recurrence was observed in 5.3% of postmenopausal women who had HR-positive breast cancer within the first 3 years of adjuvant tamoxifen therapy. Two groups of patients were identified clearly, as expected. First, 8.2% of patients who had lymph node-positive, mSBR grade 2 or 3 tumors developed an early systemic recurrence, and this rate reached 15.6% among patients who had lymph node-positive, grade 3 tumors. These results must be interpreted with caution, because no patients had received adjuvant chemotherapy according to the standard treatment procedures during the time frame of recruitment. Meanwhile, several randomized trials have demonstrated a significant improvement in DFS with anthracycline-based, chemoendocrine therapy compared with tamoxifen alone in postmenopausal women with HR-positive breast cancer.20–23 Conversely, we also identified a large subset of patients (40%) with a very low risk of early recurrence, ie, patients with lymph node-negative and/or mSBR grade 1 tumors. However, the absence of early recurrence in lymph node-negative patients does not preclude the risk of later distant recurrence, which reaches a 10-year incidence of 30% according to previously published data.24, 25 Indeed, it has been demonstrated that several factors have a nonproportional effect on hazards.26–28 The ER level is a major concern, because positive ER status has been associated with a protective effect on recurrences within the first 3 years, but that association switches to a negative effect on disease outcome after 3 years.27 Consequently, the commonly used Cox proportional-hazards regression may not be the best statistical method for the analysis of prognostic factors in patients with breast carcinoma. Considering only events that occur over a restricted period is one way to limit the impact of a violation of proportional hazards rules.27
The analysis of early recurrence in a cohort of homogeneously tamoxifen-treated patients also has provided information regarding which factors are were predictive of resistance to treatment. Negative PgR status has been linked to a decreased benefit of tamoxifen in the metastatic setting29 and in the adjuvant setting, in which a greater benefit from anastrozole versus tamoxifen was reported in ER-positive/PgR-negative subgroups compared with ER-positive/PgR-positive subgroups.30 Conversely, no interaction between treatment effect and PgR expression was reported by the BIG 1–98 trial in a comparison of tamoxifen versus letrozole.11 Because the overexpression of HER2 and EGFR has been associated with a low response to tamoxifen in both metastatic and neoadjuvant settings,31–35 the indication for adjuvant tamoxifen also is controversial in patients who present with those features. In our analysis, we did not notice a significantly increased incidence of negative PgR status in patients who developed an early distant recurrence. Furthermore, exploratory immunohistochemical analyses performed on primary tumors that recurred during tamoxifen treatment did not reveal any unusual expression of EGFR, HER2, or VEGF-R2 that could have suggested a role in tamoxifen resistance.18 However, we did not compare the incidence of marker expression between tumors from patients who recurred and patients who did not recur, making it difficult to draw any conclusions. Genetic variation in tamoxifen-metabolizing enzymes may be another important factor to consider. Tamoxifen is converted by the cytochrome P450 enzyme 2D6 (CYP2D6) in antiestrogenic metabolites, which are more potent than tamoxifen itself. Thereby, women with a low activity of CYP2D6 may develop a substantial decrease in tamoxifen activity.36 Recently, a study of 256 patients with breast cancer who had received adjuvant tamoxifen for 5 years indicated that patients who had 2 variants of CYP2D6 alleles (7% of patients) had a higher risk of recurrence than patients who had 1 or 2 normal alleles.37 An immediate, broad peak in the recurrence-free survival hazard rate was observed for patients with decreased metabolism. In contrast, the hazard rate for patients with high metabolism was reduced and did not peak until almost the fourth year.37
AI therapy is recommended widely for postmenopausal women with HR-positive breast cancer, although the optimal strategy remains under discussion. Hopefully, mature results from the BIG 1–98 and Tamoxifen Exemestane Adjuvant Multinational (TEAM) trials will provide a conclusive answer. Meanwhile, the choice of a therapeutic strategy is required. To date, the only tools at our disposal are 2 mathematic modeling estimates.38–40 These models have reported conflicting results, probably because of methodological differences in the definition of endpoints and a possible carryover effect of AI therapy beyond 5 years of treatment. The surface model favored an upfront treatment with AI,38 whereas the sequential strategy appeared to be preferable for patients with ER-positive/PgR-positive tumors according to the Markov model.39, 40 These estimations must be interpreted carefully interpreted because of the limitations of such modeling.
The safety profile of endocrine therapy also should be considered. With regard to upfront treatments, the results from 2 substudies of the TEAM and ATAC trials did not indicate any major differences in terms of quality of life between AI and tamoxifen.41, 42 Nevertheless, women who received AI reported fewer cold sweats and vaginal discharge but presented with more vaginal dryness, painful intercourse, and loss of sexual interest compared with women who received tamoxifen. Muscular and joint pains also were more frequent with AI. For long-term toxicity, a potential advantage of sequential strategy may be the decrease in cumulative toxicities, such as thromboembolic diseases and endometrial carcinoma related to tamoxifen or cardiovascular risk with AI. It is a major concern that the risk of osteoporosis and clinical fractures were increased with the use of AIs, regardless of treatment strategies. The onset of endocrine therapy with tamoxifen, which increases bone mineral density, may be of interest in women who have preexisting osteoporosis, and the results of ongoing trials are awaited. In addition, it has been demonstrated that vitamin D is a potent stimulator of CYP19 (P450 aromatase gene) transcription, although prophylaxis with vitamin D in AI-treated patients requires further assessment before it can be recommended.43 The current lack of knowledge about the potential long-term side effects of AIs, including their impact on cognitive function,44 also should be considered. Finally, the results from 2 recent analyses indicted that 3 years of AI subsequent to 2 years of tamoxifen were associated with the lowest cost/quality-adjusted life years, regardless of the type of costs, ie, costs related to the risk of fractures or recurrences.45, 46
Results have shown that the upfront strategy provided a reduction of approximately 2% in metastatic recurrences within the first 3 years of treatment compared with tamoxifen.10, 11 Therefore, the identification of patients who have a high risk of distant recurrence is crucial in the choice between upfront and sequential treatments. An important finding of our analysis is the identification of patient subsets that present with low risk or high risk of early recurrence during tamoxifen therapy. Despite differences in methodology and inclusion criteria, 3 recent retrospective analyses that addressed this topic converged on similar conclusions: The risk of early recurrence during tamoxifen or toremifen therapy was correlated highly with axillary lymph node involvement.47–49 A high histoprognostic grade was associated significantly with an increased risk of early recurrence, regardless of studies, and remained significant in 2 studies according to multivariate analyses.48 Along with tumor volume and proliferation markers, HR status should be considered as an independent marker of early recurrence (Table 6).47, 48
|Variable||Current study||McArthur et al., 200547||Mauriac et al., 200648||Chagpar et al., 200649|
|No. of patients||715||4159||5980||938*|
|Types of recurrence analyzed||Distant||Local and distant||Local and distant||Distant|
|Study period, y||3||2.5||2||34 mo (median follow-up)|
|Risk factors (multivariate analysis)||Positive LN status, tumor grade||No. of positive axillary LNs; level of ER positivity||Positive LN status; negative ER and PgR status; tumor grade; HER2 overexpression/amplification; tumor size; type of endocrine treatment; vascular invasion||No. of positive axillary LNs|
In conclusion, the optimal strategy for hormonal adjuvant treatment of postmenopausal women currently is discussed, and results from the 4-arm BIG 1–98 and TEAM studies are warranted. Waiting for clearer answers, the choice between upfront and sequential strategies with AIs should be based on different parameters, including menopausal status, knowing the risk of ovarian function recovery, predictive factors of early recurrence, comorbidities, safety profile, cumulative toxicities, and cost. Our findings, in association with the results from 3 other analyses, indicated clearly that the most important criteria to be considered for the risk of early recurrence during tamoxifen treatment were lymph node status and histoprognostic tumor grade. The analysis of genetic variations in tamoxifen-metabolizing enzymes may be an important concern in the prediction of tamoxifen sensitivity.
Supported by grants from Pfizer, France. Isabelle Chapelle-Marcillac provided editorial assistance in the preparation of the article.
- 2Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group. Cancer. 1998; 83: 1142–1152., , , et al.
- 12Switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-responsive early breast cancer: a meta-analysis of the ARNO 95 trial, ABCSG Trial 8, and the ITA trial. San Antonio Breast Cancer Symp. 2005: 18. Abstract 2073., , , et al.
- 18Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer. J Clin Oncol. 2005; 23: 4695–4704., , , et al.
- 20Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). San Antonio Breast Cancer Symp. 2004. Abstract 37., , , et al.
- 22Disease-free survival advantage of weekly epirubicin plus tamoxifen versus tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6-year follow-up results of the French Adjuvant Study Group 08 trial. J Clin Oncol. 2004; 22: 4622–4630., , , et al.
- 23Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: results of French Adjuvant Study Group 02 and 07 trials. Ann Oncol. 2006; 17: 65–73., , , et al.
- 35Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005; 23: 5108–5116., , , et al.
- 41Final analysis of a planned comparison of menopausal symptoms in 1618 patients receiving either exemestane (E) or tamoxifen (T) in a blinded adjuvant hormonal study. San Antonio Breast Cancer Symp. 2005. Abstract 2039., , , et al.
- 47Risk of early relapse in post-menopausal women with early stage, estrogen receptor positive (ER+) breast cancer on tamoxifen. San Antonio Breast Cancer Symp. 2005. Abstract 3001., , , et al.
- 48Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG-1-98 trial. Ann Oncol. In press., , , et al.