# Evaluating distant recurrence‐free survival and location of metastasis in HER2+ breast cancer by ER status

## TL;DR

This study shows that the combination of HER2 and ER status in breast cancer affects long-term survival and increases the risk of brain metastasis.

## Contribution

The study reveals a time-varying interaction between HER2 and ER status affecting survival and metastasis location in breast cancer.

## Key findings

- HER2+ patients with ER+ status show improved long-term survival compared to HER2− patients.
- HER2+ patients have a higher risk of brain metastasis compared to HER2− patients.
- The interaction between HER2 and ER status impacts distant recurrence-free survival in a time-dependent manner.

## Abstract

Prognostic factors, such as the Human Epidermal growth factor Receptor 2 (HER2) and Estrogen Receptor (ER) influence distant recurrence‐free survival (RFS) in breast cancer. This study aims to evaluate the interaction between HER2 and ER status with RFS, and if that interaction influences where the metastasis is located. To do this, we used a study population of all women diagnosed with non‐metastatic, invasive breast cancer in Stockholm from 2007 to 2020. Flexible parametric survival models were used to estimate time‐varying survival and hazard ratios (HR) for RFS. Cumulative incidence was used to quantify rates of metastasis in key locations. We found significant interactions between ER and HER2 for RFS (p = 0.037), which was time varying (p = 0.017). For ER+ patients, adjusted short‐term survival at 2.5 years after diagnosis was identical for HER2+ compared to HER2− patients (HR 1.02, CI; 0.76–1.39), but was dramatically better for HER2+ patients after 5 years (HR at 7.5 years 0.29, CI; 0.14–0.58). In contrast, among ER− patients, HER2+ patients experienced constant risk compared to HER2− from diagnosis until the end of the study (HR ~0.50). Finally, we observed that HER2+ patients have a higher rate of first metastasis to the brain than HER2− patients (p < 0.001). Our study demonstrates that the interaction between ER and HER2 status has a time‐varying impact on RFS and plays a role in determining the location of metastasis. Thus, the utilization of complex models that combine ER and HER2 status can enhance the understanding of patient RFS and the likelihood of metastasis in specific locations.

The prognostic significance of the presence or absence of human epidermal growth factor receptor 2 (HER2) and estrogen receptor (ER) in breast cancer is well‐established. However, the relationship of HER2 and ER with distant disease recurrence and metastasis location is less well understood. This study examined interactions between distant recurrence‐free survival (RFS), metastasis site, and HER2 and ER status. Receptor status was found to interact significantly with RFS in a time‐dependent manner, with combined HER2 and ER status impacting metastasis location. This was most notable for HER2+ cancers, for which increased likelihood of brain metastasis was detected.