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Keywords:

  • estrogen receptor;
  • progesterone receptor;
  • local recurrence;
  • locoregional recurrence;
  • breast cancer

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

Estrogen receptor (ER) and progesterone receptor (PR) are important prognostic and predictive biomarkers in breast cancer. Patients with tumors positive for either receptor are generally considered hormone receptor-positive for treatment decisions. However, some data suggest that patients with ER+/PR or ER/PR+ tumors may have worse outcomes than those with ER+/PR+ tumors. Few data correlate these biomarkers with locoregional (LR) recurrence.

METHODS:

The authors retrospectively reviewed records of 635 patients with T1a,bN0 disease who received definitive treatment at their institution between 1997 and 2002 and had archival tissue blocks for prospective assessment of ER/PR expression. They compared clinical outcomes of the 479 patients with ER+/PR+ disease to the 156 patients with ER+/PR or ER/PR+disease.

RESULTS:

LR recurrence rates were higher in patients with 1 receptor positive compared with ER+/PR+ (7-year rate: 8.8% vs 2.5%, P = .024). There was no difference between the 2 groups in the rates of distant metastasis (DM) (P = .531) or overall survival (P = .491). One positive receptor predicted for LR recurrence in patients who did not receive hormonal therapy (P = .046), but not in patients who received hormonal therapy (P = .296). On multivariate analysis, 1 positive receptor predicted for LR recurrence in the overall group (hazard ratio, 2.81; 95% confidence interval, 1.06-7.48; P = .038).

CONCLUSIONS:

Patients with T1a,bN0 breast cancer with only 1 positive hormone receptor have increased rates of LR recurrence compared with patients with ER+/PR+ disease, although this difference may be reduced or eliminated with systemic treatment. In contrast, the authors found no evidence of an increased rate of DM in these patients with favorable disease stage. Cancer 2011. © 2010 American Cancer Society.

Estrogen receptor (ER) and progesterone receptor (PR) are important prognostic and predictive biomarkers in breast cancer patients.1, 2 Patients with hormone receptor-negative disease have a higher risk of mortality compared with those with hormone receptor-positive disease.3 Moreover, the roles of ER/PR in predicting response to hormonal therapy are well established.4 Although it has been shown that patients with ER+/PR+ disease have less early recurrence and greater response to hormonal therapy compared with patients with ERPR disease, it is less clear whether patients with tumors that are ER+/PR or ER/PR+ have different outcomes than those with ER+/PR+ tumors. Tumors with either ER or PR expression have been shown to respond to hormonal therapy5, 6; therefore, patients with tumors that are ER+ or PR+ are generally considered hormone receptor positive with respect to treatment decisions.7

In the present study, we analyzed patients with lymph node-negative disease, and tumors ≤1 cm. Although previous studies have evaluated hormone receptor status as a marker of recurrence, few have focused specifically on this patient population, as the recurrence rates in this group are generally low. However, widespread mammographic screening has led to an increase in the early stage breast cancer patient population.8 As this patient population continues to grow, it will be important to identify factors that increase recurrence risk to guide management recommendations about which subsets of this population should receive systemic treatments.

In outcome studies that examine hormone receptor status, it is important to consider the quality of biomarker assessment, and essential that these biomarkers be accurately and uniformly assessed. Nonuniform methods of ER and PR assessment may result in inconsistent data.2, 9 Mislabeling of biomarker status is a significant confounding factor in many prospective and retrospective analyses. This is an important consideration, in that most retrospective studies have not included prospective, centralized, and uniform assessment of ER and PR status.

Previous studies, including recent work by our group, have correlated ER, PR, and human epidermal growth receptor 2 (HER2) status with rates of survival and distant recurrence.10 However, fewer studies have examined these biomarkers as predictors of locoregional (LR) recurrence. In a recent analysis, we found that patients with ER/PR-negative or HER2-positive T1a,bN0 breast cancer have a higher risk of LR recurrence than patients without these tumor features.11 In the present study, we compared outcomes between patients with ER+/PR+ disease and those with ER+/PR or ER/PR+ disease using uniform evaluation of ER and PR expression. We aimed to evaluate whether patients with only 1 hormone receptor positive were at higher risk of recurrence and therefore may benefit from adjuvant systemic treatment or more aggressive local treatment.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Patient Population

The Breast Cancer Management System database of The University of Texas M. D. Anderson Cancer Center was used to identify consecutive patients with newly diagnosed lymph node-negative, invasive breast cancers, 1 cm or smaller, diagnosed between 1997 and 2002. Patients with recurrent breast cancer at presentation were excluded. Of the 911 patients identified, 155 were excluded from the analysis because of incomplete receptor information and inability to obtain tissue for biomarker analyses. Of the 756 remaining patients, 121 were ER/PR and were excluded from this study to compare those who were positive for 1 receptor versus both receptors. This resulted in 635 patients who were included in the analysis. Patients were included regardless of the type of locoregional treatment received. A total of 404 patients underwent breast-conserving surgery (380 patients received adjuvant radiation therapy, 15 had unknown radiation therapy status, and 9 patients refused radiation). The standard radiotherapy approach for breast-conservation patients during the study period was to treat the whole breast to 50 grays (Gy) in 25 fractions using medial and lateral tangent fields, followed by a tumor bed boost of 10 Gy in 5 fractions. In addition, 231 patients underwent mastectomy (5 patients received adjuvant radiation therapy).

Pathology Methods

All available hematoxylin and eosin (H&E)-stained sections were retrospectively evaluated by 2 breast pathologists (M.G. and A.S.). When the original H&E-stained slides were not available, new sections were performed from paraffin-embedded tissue blocks, and histopathologic features were evaluated for the purpose of this research. Immunohistochemical analysis was performed to determine hormone receptor status using standard procedures on 4 μm sections of paraffin-embedded tissues stained with monoclonal antibodies for estrogen and progesterone receptors (6F11 antibody [Novacastra Laboratories, Newcastle Upon Tyne, UK] and pgR1294 antibody [Dako, Carpentaria, Calif]). Nuclear staining ≥10% was considered a positive result. Interpretation of ER and PR staining was done without any knowledge of LR recurrence or other outcome measures.

Statistical Methods

The clinical outcomes analyzed in this study were LR recurrence, distant metastasis (DM), and overall survival (OS). LR recurrence was defined as recurrence within the ipsilateral breast, ipsilateral chest wall, or ipsilateral regional lymph nodes, including axillary, supraclavicular, and internal mammary nodes. Time to recurrence or death was computed from the date of diagnosis. Time to recurrence was censored at last follow-up date for patients without recurrence. Patients who died before experiencing a disease recurrence were censored at the date of death. Time to recurrence was estimated by the Kaplan-Meier method and compared by the log-rank statistic.12 Multivariate analyses were performed using the Cox proportional hazards model.13P values <.05 were considered statistically significant. All calculations were performed using Stata 10 software (StataCorp, College Station, Tex).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Patient characteristics are summarized in Table 1. Median age at diagnosis was 56 years, with an age range of 26 to 87 years. Overall, 75% of patients had tumors that were positive for both hormone receptors (ER+/PR+ ), 21% had ER+/PR tumors, and 4% had ER/PR+tumors. Because there were so few patients with ER/PR+ status (4%, n = 27), all patients with only 1 positive hormone receptor were grouped together for the present analysis. Compared with patients with tumors that had only 1 receptor positive, those with ER+/PR+ disease were more likely to have T1b disease (P = .001) and were marginally more likely to be <50 years old at diagnosis (P = .051). Those with 1 receptor positive were more likely to have higher nuclear grade (P = .009), and marginally more likely to receive adjuvant chemotherapy (P = .053). There was no difference between the 2 groups with respect to race, histology, HER2 status, adjuvant hormonal therapy, surgery type, or margin status.

Table 1. Patient Characteristics
CharacteristicER and PR StatusP
1 PositiveER+/PR+
No.%No.%
  1. ER indicates estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth receptor 2.

Age, y
 <503421.8%14329.9% 
 ≥5012278.2%33670.1%.051
Race
 Black138.3%326.7% 
 Hispanic149.0%439.0% 
 Other63.8%153.1% 
 White12378.8%38981.2%.869
Histology
 Ductal12278.2%36876.8% 
 Lobular149.0%367.5% 
 Mixed74.5%183.8% 
 Other138.3%5711.9%.601
T stage
 T1a7044.9%14329.9% 
 T1b8655.1%33670.1%.001
Nuclear grade
 12518.4%7217.2% 
 26648.5%25961.8% 
 34533.1%8821.0%.009
HER2
 Negative14190.4%44793.3% 
 Positive159.6%326.7%.224
Adjuvant chemotherapy
 No14291.0%45695.2% 
 Yes149.0%234.8%.053
Adjuvant hormonal therapy
 No5535.3%15432.2% 
 Unknown21.3%1.2% 
 Yes9963.5%32467.6%.172
Adjuvant systemic (hormonal or chemotherapy)
 No5032.5%14730.8% 
 Yes10467.5%33169.2%.69
Surgery type
 Breast conserving9158.3%31365.3% 
 Mastectomy6541.7%16634.7%.114
Margin status
 Negative14794.2%45695.2% 
 Close (<2 mm)/positive95.8%214.4% 
 Unknown0.0%2.4%.565

With a median follow-up time of 6.0 years (range, 0.1-10.8 years) for surviving patients, there were a total of 26 recurrences, including 17 locoregional recurrences and 9 distant recurrences, as well as 39 total deaths. Of the 17 locoregional recurrences, 11 were ipsilateral breast, 3 were supraclavicular, 2 were chest wall, and 1 was axillary. On Kaplan-Meier analysis, there was an observed difference between the distribution of LR recurrence events between patients who had tumors that were ER+/PR+ compared with those with ER+/PR or ER/PR+ tumors. Figure 1 compares LR recurrence rates between patients with tumors that had 1 receptor positive versus ER+/PR+, and reveals that patients with only 1 positive receptor have a higher rate of LR recurrence (7-year rate, 8.8% vs 2.5%; P = .024). When stratifying the patients by local treatment type (breast-conserving therapy [BCT] vs mastectomy), the same trend toward increased LR recurrence in the patients with only 1 positive receptor was seen in both the BCT and mastectomy cohorts. However, due to the relatively low number of LR recurrence events, these differences did not reach statistical significance (P = .121 for BCT, and P = .087 for mastectomy). After adjustment for other patient and disease characteristics in a Cox regression analysis, 1 positive receptor independently predicted for LR recurrence in the overall group (hazard ratio, 2.81; 95% confidence interval [CI], 1.06-7.48; P = .038). In addition, close/positive margins (<2 mm) and age <50 years predicted for LR recurrence in the multivariate model (Table 2).

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Figure 1. Locoregional recurrence (LRR) rates by estrogen receptor (ER) and progesterone receptor (PR) status are shown.

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Table 2. Multivariate Analysis
CharacteristicHazard Ratio95% CIP
  1. CI indicates confidence interval; ER, estrogen receptor; PR, progesterone receptor.

One positive (vs ER+/PR+)2.81(1.06-7.48).038
Age <50 vs ≥50 y3.60(1.36-9.52).010
Close/positive vs free margins4.36(1.22-15.52).023

To determine whether LR recurrence was increased in both the ER+/PR and ER/PR+ subgroups in the cohort with only 1 positive receptor, the analysis was repeated after separating the patients with ER+/PR and ER/PR+ disease. The trend toward increased LR recurrence compared with ER+/PR+ patients was seen in both the ER+/PR subgroup and the much smaller ER/PR+ subgroup, but did not reach statistical significance (compared with ER+/PR+: P = .054 for ER+/PR and P = .079 for ER/PR+).

To determine whether receiving adjuvant hormonal therapy affected LR recurrence rates, Kaplan-Meier analysis was repeated, and patients were grouped by hormonal therapy status. Overall, 67% of patients received hormonal therapy. Of the 423 patients who received hormonal therapy, 349 received tamoxifen, 60 received an aromatase inhibitor (AI), 9 received both tamoxifen and an AI, and 5 received an unknown hormonal therapy agent. There was no significant difference between the 2 groups in percentage of patients who received hormonal therapy (Table 1). Interestingly, the difference in LR recurrence between patients with 1 receptor positive versus ER+/PR+ was significant among patients who did not receive hormonal therapy (7-year rate, 13.3% vs 3.4%; P = .046) (Fig. 2A), but not in those who received adjuvant hormonal therapy (7-year rate: 5.7% vs 2.1%, P = .296) (Fig. 2B).

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Figure 2. Locoregional recurrence (LRR) rates by estrogen receptor (ER) and progesterone receptor (PR) status are shown in patients who (A) did not receive hormonal therapy and (B) did receive hormonal therapy

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Rates of OS and DM were also compared between the 2 groups in a Kaplan-Meier analysis. Distant metastasis was uncommon in both groups, and the difference was not statistically significant (7-year rate, 4.2% [1 positive] vs 1.6% [ER+/PR+]; P = .531) (Fig 3A). OS was similar between the 2 groups, with 7-year OS of 92.6% in patients with 1 receptor positive, and 93.5% in patients with both receptors positive (P = .491) (Fig. 3B). In addition, rates of OS and distant metastasis were the same between the 2 groups, regardless of whether patients received BCT or mastectomy.

thumbnail image

Figure 3. Rates of (A) distant metastasis (DM) and (B) overall survival (OS) by estrogen receptor (ER) and progesterone receptor (PR) status are shown.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

In this study, we demonstrated that breast cancer patients with T1a,bN0 disease that has only 1 positive hormone receptor have a higher risk of LR recurrence than patients with both receptors positive. These data suggest that PR status in addition to ER status may have prognostic significance for LR recurrence, even in patients with very small tumors and negative lymph nodes. However, this difference is only observed in patients who did not receive hormonal therapy. There was not a significant difference when only considering patients who received hormonal treatment. In addition, there was no difference in DM or OS between the 2 groups.

ER negativity has been previously correlated with LR recurrence. We recently reported that ER negativity, as well as PR negativity, predicts for LR recurrence in the T1a,bN0 population.11 In addition, in a recursive partitioning analysis studying the endpoint of LR recurrence after postmastectomy radiation, our group previously reported that ER-negative disease was the most important factor predicting for LR recurrence.14 These data suggest that patients with hormone receptor-negative disease may require additional systemic therapy or more aggressive local therapy. Interestingly, an analysis of patients enrolled in 5 National Surgical Adjuvant Breast and Bowel Project randomized controlled trials showed that chemotherapy can decrease LR recurrence rates among ER patients.15 This study included a patient population similar to the present study's—patients with tumors ≤1 cm, and negative lymph nodes. Specifically, the addition of chemotherapy to surgery decreased LR recurrence rates from 8% to 4% in this population. In patients who underwent breast conservation therapy, the addition of chemotherapy to lumpectomy and radiation decreased ipsilateral breast tumor recurrence from 8% to 3%. These data demonstrate that systemic therapy can be effective in reducing LR recurrence rates.

The predictive value of PR in patients who have ER+ tumors and receive hormonal therapy has been previously validated in a prospective trial of 342 patients with metastatic disease. Southwest Oncology Group protocol 8228 demonstrated that elevated PR levels independently correlated with response to tamoxifen, longer time to treatment failure, and improved OS.16 A large retrospective database study that examined patients with early stage disease who received hormonal therapy, as well as those who did not, had similar findings. The prognostic value of PR in addition to ER in patients who did not receive hormonal therapy was modest with respect to disease-free survival and OS. However, PR status was a significant independent predictor of disease-free and OS in patients who received hormonal therapy.17 In addition, a study based on the National Cancer Institute's Surveillance, Epidemiology, and End Results database showed that patients with 1 positive hormone receptor had breast cancer-specific survival that was better than those with ER/PR disease, but worse than those with ER+/PR+ disease. The difference was more pronounced in more advanced-stage disease, but was still significant in patients with stage I disease (hazard ratio compared with ER+/PR+: 1.53 for ER+/PR [95% CI, 1.32-1.77]; 1.66 for ER/PR+ [95% CI, 1.32-2.12]). Notably, this study did not consider whether patients received hormonal therapy and did not report LR outcome data.3

Although the prognostic and predictive value of PR in addition ER has been studied, fewer data are available regarding the value of both ER and PR with respect to LR recurrence, as most studies group patients with tumors that are positive for either receptor into the same category. One previous study has suggested that patients with tumors that have only 1 positive hormone receptor may be less responsive to hormonal therapy than those with both receptors positive, and may therefore require additional systemic therapy.17 Our data suggest that hormonal therapy may be adequate in patients with 1 positive receptor and favorable disease stage.

Because the present study is a retrospective analysis, inherent biases and limitations must be considered. To minimize bias, we evaluated all patients with T1a,bN0 breast cancer who received definitive treatment at our institution between 1997 and 2002. All patients were prospectively entered into the database during this time, and all patients who presented to our institution with recurrent disease were excluded to avoid biasing recurrence data. Because there is a generally low recurrence rate in patients with T1a,bN0 disease, 1 important limitation of the present study is the relatively low number of recurrence events. In addition, we accounted for as many confounding clinicopathologic variables as possible in the multivariate analysis, but because uniform assessment of lymphovascular space invasion was not available for all patients, this factor was not included in the analysis. Conversely, a major strength of our study is the uniform assessment of ER and PR status. Inconsistent methods of ER and PR assessment can result in data inaccuracies.2, 9 Interlaboratory variability in biomarker assessment inevitably results in the mislabeling of biomarker status and significantly confounds many prospective and retrospective studies. It is important to note that we did use a cutoff of 10% for a positive result, which was the standard at the time of our histopathologic review. However, more recent guidelines have suggested a much lower cutoff of 1%, as patients with low ER/PR positivity have been shown to benefit from hormonal therapy.18

Our data demonstrate that patients with T1a,bN0 breast cancer that has only 1 positive hormone receptor have a higher risk of LR recurrence than those with ER+/PR+ disease, but that there is no significant difference in LR recurrence between the 2 groups in patients who receive hormonal therapy. Although these patients generally have excellent outcomes, our data underscore the importance of hormonal therapy, even in patients with only 1 positive hormone receptor and the most favorable disease stage. Future studies should continue to examine the prognostic and predictive value of both ER and PR when quality uniform pathologic assessment is available, rather than simply grouping them into hormone receptor-positive and hormone receptor-negative categories.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

We thank Shu-Wan Kau, Informatics Manager for the Breast Cancer Management System database, for assistance with our data.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

This work was supported in part through a research donation from Ann and Clarence Cazalot and from National Cancer Institute grants CA16672, T32CA77060, and 1K23CA121994-01 (A.M.G.-A.).

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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