Predictive Factors for Late (>5 Years) Distant Recurrences in Hormone Receptor (HR) Positive, Human Epidermal Growth Factor Receptor 2 (HER2) Negative Breast Cancer Patients: >20 Year Follow Up

Case Report

Austin J Clin Case Rep. 2017; 4(2): 1119.

Predictive Factors for Late (>5 Years) Distant Recurrences in Hormone Receptor (HR) Positive, Human Epidermal Growth Factor Receptor 2 (HER2) Negative Breast Cancer Patients: >20 Year Follow Up

Chaudhary RJ¹, Rastogi A¹, Pahari H¹, Thiagarajan S¹, Bhangui P¹, Goja S¹, Gautam D², Piplani T³ and Soin AS¹

¹Division of Hematology and Oncology, University of Cincinnati, USA

²Division of Hematology and Oncology, Cleveland Clinic, Moll Cancer Center, USA

³Division of Hematology and Oncology, University of California, USA

4Division of Hematology and Oncology, Fairview/ Cleveland Clinic Hospital, USA

*Corresponding author: Jaskirat Randhawa, Division of Hematology and Oncology, University of Cincinnati, Cincinnati, Ohio, USA

Received: March 18, 2017; Accepted: June 15, 2017; Published: July 06, 2017


Background: Hormone Receptor (HR) positive Breast Cancer (BC) by virtue of tumor dormancy can present with delayed systemic recurrence after adjuvant therapy, frequently years after initial diagnosis. The malignant cells remain quiescent or proliferate very slowly until they progress to overt cancer.

Methods: Over 2500 charts of HR+/HER2 negative BC patients were reviewed. Patients with follow up <5 years, recurrence within 5 years and all local recurrences < or >5 years were excluded. 35 late distant recurrences were identified. Data was analyzed with 50 patients from the same group without recurrences during the same period. Following factors were used for analysis: age at diagnosis, longest tumor diameter, smoking history, clinical stage at diagnosis, Lymph Node Involvement (LNI), tumor-grade, histology, Estrogen Receptor (ER) status, Progesterone Receptor (PR) status, duration of adjuvant therapy (=5 years, >5 years ) and treatment modalities. Multivariate analysis was conducted using logistic regression and proportional hazards models.

Results: The median/mean age at diagnosis was 58/58.5 years. Tumor size, T-stage at diagnosis, and duration of adjuvant therapy were associated with late relapse (p= 0.025, p= 0.012, p= 0.037 respectively). T-stage at diagnosis was the only independent predictor identified; with an estimated odds ratio of 2.62 (95% CI: 1.22, 5.64).

Conclusion: In univariate analysis, the tumor diameter, T-stage at diagnosis and duration of adjuvant therapy are associated with both recurrence and time to relapse. Patients who received adjuvant endocrine therapy =5 years had decreased rate of late recurrences. In multivariate analysis, T-stage at diagnosis is the only independent predictor.


Breast cancer is a heterogeneous group of cancers that have varying degrees of clinical behavior and are driven by hormonal status or HER2 status. Advances in treatment of breast cancer have evolved as we have achieved a greater understanding of its molecular foundations. Despite these advances there remains a dearth of knowledge on reasons for late recurrences in hormone positive breast cancer. One prevailing hypothesis is that late distant recurrences in hormone positive breast cancer are felt to be due to tumor dormancy where malignant cells remain quiescent or proliferate very slowly until they progress to overt cancer. The delayed recurrence of hormone receptor-positive breast cancer remains a significant clinical challenge as approximately 50% of recurrences in HR-positive disease occur after the first 5 years of initial diagnosis and anti-hormonal treatment. Adjuvant treatment with endocrine therapy reduces the recurrence risk in patients with HR-positive breast cancer over all time periods by 39% but can lead to a number of adverse events that make compliance to treatment difficult [1]. For these reasons it is critically important to identify clinicopathological features that can better predict risk of late recurrence. Models such as the Breast Cancer Index (BCI) have been developed and can predict early (0-5 years) and late risk of distant recurrence in early stage breast cancer patients (ER positive and lymph node-negative breast cancer) but these models have not been developed in more advanced breast cancers and furthermore there remains a dearth of studies that have analyzed clinical factors that can predict late recurrence [2]. The aim of this study was to identify clinical and pathological factors at diagnosis that are associated with delayed systemic recurrence in hormone positive (lymph node positive and lymph node negative) breast cancer patients.

Methods and Analysis

After obtaining Cleveland Clinic Institutional Review Board (IRB) approval, we reviewed over 2500 charts of HR+/HER2 negative BC patients. The patients that were included in analysis required a biopsy proven diagnosis of hormone receptor positive (ER/PR) BC and had to have a minimum follow up of 5 years or more. Patients were excluded if they had relapse <5 years or had follow up less than 5 years. In study group only late (>5 years) and distant metastases were included. All local recurrences or contra lateral breast recurrences (less than 5 years or more than 5 years) were excluded. Amongst the 2500 charts reviewed we identified 35 patients (study group) that met our inclusion criteria. We chose 50 patients (control group) who did not relapse and had similar follow up period as compared to study group. As an example of how this was done, we identified a patient who had developed distant metastatic disease 7 years after diagnosis and the patient that was picked for the control group also had 7 years follow up and no distant metastatic disease or no evidence of recurrence at 7 years. All of the patients that were included in this analysis were followed for at least 5 years, so results of this analysis were conditional on patients being alive and disease free 5 years from their initial diagnosis.

The goals of the analysis were:

1. To identify differences in clinical and pathological features between those who had a distant late relapse versus those who did not.

2. To determine if there are any independent predictors of future relapse.

All analyses that were performed were two-tailed and were performed at a significance level of 0.05. SAS 9.3 software (SAS Institute, Cary, NC) was used for all analyses.

The following parameters were used for univariable analysis: age at diagnosis, tumor diameter, smoking history, overall stage at diagnosis, T stage at diagnosis, lymph nodes, tumor grade, histology, estrogen/progesterone receptor, duration of adjuvant therapy and treatments received. Univariable associations between recurrences and clinical features were assessed using Wilcoxon rank sum, Kruskal-Wallis tests and Chi-square tests. Multivariable analysis was conducted using a logistic regression model with forward selection. Time to event data was analyzed using proportional hazards models. Time to relapse was measured from the date of diagnosis to the date of relapse or last follow-up (Table 1 and 2).