24O - Increased long-term risk of fatal breast cancer in patients with high intra-tumor heterogeneity of the estrogen receptor – Retrospective analyses o...

Date 04 May 2017
Event IMPAKT 2017
Session Best abstracts session – Oral abstracts
Topics Breast Cancer
Translational Research
Presenter Linda Lindström
Authors L.S. Lindström1, C. Yau2, N. Yu1, K. Czene3, B. Nordenskjöld4, O. Stål4, C.C. Benz2, T. Fornander5, A.D. Borowsky6, L. Esserman2
  • 1Department Of Biosciences And Nutrition, Karolinska Institutet, 141 83 - Stockholm/SE
  • 2Department Of Surgery, University of California at San Francisco, 94115 - San Francisco/US
  • 3Department Of Medical Epidemiology And Biostatistics, Karolinska Institutet, 17177 - Stockholm/SE
  • 4Department Of Clinical And Experimental Medicine, Linköping University, 581 83 - Linköping/SE
  • 5Department Of Oncology-pathology, Karolinska Institutet, 171 77 - Stockholm/SE
  • 6Center For Comparative Medicine, University of California at Davis, 95616 - Davis/US

Abstract

Body

Background

It has been suggested that breast cancer tumors possess intra-tumor heterogeneity with varying metastatic capacity. Here, we aimed to determine whether high intra-tumor heterogeneity of the estrogen receptor (ER) predicts an increased long-term risk (25 years) of fatal breast cancer.

Methods

The Stockholm Tamoxifen (STO-3) trial enrolled postmenopausal lymph node-negative breast cancer patients randomized to receive adjuvant tamoxifen versus not. All patients had a complete long-term follow-up until December 31, 2012. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists (ER reassessed in 2014), and intra-tumor heterogeneity of ER was calculated using Rao’s quadratic entropy.

Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER in ER-positive and Luminal A (by gene expression, Agilent array) patients were performed using Kaplan-Meier and multivariate Cox proportional hazard modeling adjusting for patient and tumor characteristics.

Findings

A statistically significant difference in long-term survival with intra-tumor heterogeneity of ER and trial arm was seen for all ER-positive patients (Log rank, P<0.0001), and for patients with Luminal A subtype tumors (Log rank, P=0.012). Furthermore, patients with high intra-tumor heterogeneity of ER had a two-fold increased long-term risk of fatal breast cancer as compared to patients with low intra-tumor heterogeneity (Hazard ratio [HR], 1.98; 95% CI, 1.31-3.00). A similar risk increase was seen for patients with Luminal A subtype with high intra-tumor heterogeneity of ER compared to patients with low heterogeneity (HR, 2.43; 95% CI, 1.18-4.99).

Interpretation

Patients with high intra-tumor heterogeneity of ER had an increased long-term risk of fatal breast cancer as compared to patients with low intra-tumor heterogeneity. Therefore, routine clinical assessment of intra-tumor heterogeneity of ER may identify patients with ER-positive disease at high long-term risk for fatal breast cancer, potentially changing clinical management especially for patients with Luminal A subtype tumors.

Clinical trial identification

The STO-3 trial was performed before (started 1976 until 1990) the use of standard trial protocol number was introduced.