Clinical Investigation
Estrogen/Progesterone Receptor Negativity and HER2 Positivity Predict Locoregional Recurrence in Patients With T1a,bN0 Breast Cancer

Presented at the American Society for Radiation Oncology 51st Annual Meeting, Chicago, IL, November 2, 2009.
https://doi.org/10.1016/j.ijrobp.2009.12.011Get rights and content

Purpose

Data have suggested that the molecular features of breast cancer are important determinants of outcome; however, few studies have correlated these features with locoregional recurrence (LRR). In the present study, we evaluated estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as predictors of LRR in patients with lymph node-negative disease and tumors ≤1 cm, because these patients often do not receive adjuvant chemotherapy or trastuzumab.

Methods and Materials

The data from 911 patients with stage T1a,bN0 breast cancer who had received definitive treatment at our institution between 1997 and 2002 were retrospectively reviewed. We prospectively analyzed ER/PR/HER2 expression from the archival tissue blocks of 756 patients. These 756 patients represented the cohort for the present study.

Results

With a median follow-up of 6.0 years, the 5- and 8-year Kaplan-Meier LRR rate was 1.6% and 5.9%, respectively, with no difference noted in those who underwent breast conservation therapy vs. mastectomy (p = .347). The 8-year LRR rates were greater in the patients with ER-negative (10.6% vs. 4.2%, p = .016), PR-negative (9.0% vs. 4.2%, p = .009), or HER2-positive (17.5% vs. 3.9%, p = 0.009) tumors. On multivariate analysis, ER-negative and PR-negative disease (hazard ratio, 2.37; p = .046) and HER2-positive disease (hazard ratio, 3.13, p = .016) independently predicted for LRR.

Conclusion

Patients with ER/PR-negative or HER2-positive T1a,bN0 breast cancer had a greater risk of LRR. Therapeutic strategies, such as the use of chemotherapy and/or anti-HER2 therapies, should be considered for future clinical trials for these patients.

Introduction

Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) have proved to be important independent prognostic and predictive biomarkers in breast cancer 1, 2. Patients with hormone receptor (HR)-negative disease have a greater risk of mortality than those with HR-positive disease (3). Similarly, HER2-positivity predicts for recurrence and mortality in breast cancer patients who have not received systemic therapy 4, 5, 6. Furthermore, the roles of ER/PR in predicting the response to hormonal therapy (7) and HER2 in predicting the response to trastuzumab and systemic chemotherapy (8) have been well-established.

When examining the ER, PR, and HER2 status of tumors, it is important to consider the quality of biomarker assessment. In long-term outcome studies, it is essential that these biomarkers be accurately and uniformly assessed. An analysis of two major randomized controlled trials revealed a 26% (9) and an 18% (10) discordance between the local and central pathologic assessment of HER2 status. Similarly, nonuniform methods of ER and PR assessment can result in inconsistent data 2, 11. Mislabeling of biomarker status has been a significant confounding factor in many prospective and retrospective analyses that have assessed the importance of these biomarkers in determining outcome. This is an important consideration because most retrospective studies have not included prospective, centralized, and uniform assessment of ER, PR, and HER2 status.

In the present study, we analyzed patients with node-negative disease and tumors ≤1 cm. Although previous studies have evaluated ER, PR, and HER2 status as markers of recurrence, few have focused specifically on this patient population, because the recurrence rates in this group have generally been low. However, widespread mammographic screening has led to an increase in the early-stage breast cancer patient population (12). As this patient population continues to increase, it will be important to identify factors that increase recurrence risk in order to guide management recommendations. At present, consensus guidelines, such as the National Comprehensive Cancer Network Clinical Practice Guidelines, do not recommend adjuvant chemotherapy or anti-HER2 therapy for stage T1aN0 tumors and have only suggested considering these systemic therapies for patients with HER2-positive T1bN0 disease and additional unfavorable features, such as HR-negative tumor, lymphovascular space invasion, or moderately/poorly differentiated tumors (13). Patients with stage T1a,bN0 disease were excluded from most of the large, randomized controlled trials that established the role of trastuzumab in early-stage breast cancer 11, 14, 15, 16, 17. Accordingly, patients with Stage T1a,bN0 disease often do not receive adjuvant chemotherapy or trastuzumab.

Previous studies, including recent work by our group, have correlated biomarker status with rates of survival and distant recurrence (18). However, fewer studies have examined these biomarkers as predictors of locoregional recurrence (LRR). We aimed to identify patients who had an increased risk of LRR and therefore might benefit from adjuvant systemic treatment or more aggressive local treatment. To our knowledge, the present study is the first to evaluate patients with Stage T1a,bN0 disease for LRR using uniform evaluation of ER, PR, and HER2 expression.

Section snippets

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 node-negative, invasive breast cancer, ≤1 cm, and 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 an inability to obtain tissue for biomarker analyses (of these 155

Results

The demographic information and clinical characteristics of the patient population are summarized in Table 1. The median age at diagnosis was 56 years (range, 26–87). Of the 756 patients, 10% had HER2-positive, 80% had ER-positive, and 67% had PR-positive disease; 62% of patients had undergone BCT and 38% mastectomy; and 59% had received adjuvant hormonal therapy and 8% adjuvant chemotherapy. No patients had received adjuvant trastuzumab therapy.

With a median follow-up of 6.0 years, a total of

Discussion

In the present study, we have demonstrated that breast cancer patients with stage T1a,bN0 disease that is ER/PR-negative or HER2-positive have a greater risk of LRR than patients without these tumor features. These data have clinical relevance because they suggest that these tumor subtypes are more clinically aggressive, even in patients with very small tumors and negative lymph nodes. In addition, these data could ultimately have therapeutic implications in this patient population that has

Acknowledgments

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

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