37MO - HER2-low heterogeneity and its impact on benefit from trastuzumab deruxtecan in metastatic breast cancer

Background

Trastuzumab deruxtecan (T-DXd) has been approved for patients with HER2-low metastatic breast cancer. A common HER2 discordance exists between primary and metastatic lesions within the same patient. However, there is still controversy over which specimen should be used to determine HER2 status in guiding T-DXd treatment.

Methods

Patients with breast cancer whose HER2 status was available for both primary tumors and matched metastases were included for HER2 discordance evaluation (n=2,156). Among these, 165 patients received T-DXd treatment were divided into three cohorts based on their HER2 expression in primary and matched metastases: cohort 1 (HER2-positive/low in both primary and metastases), cohort 2 (HER2-positive/low in primary and HER2-zero in metastases), and cohort 3 (HER2-zero in primary and HER2-positive/low in metastases). Endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate, and clinical benefit rate.

Results

A high HER2 discordance rate (25.5%, K=0.37) was observed between primary and matched metastases, with independent risk factors including pathological grade, hormone receptor status, metastatic site, and metastasis time. We developed a HER2-Low Discordance Prediction (HeLP) tool (https://helptool.shinyapps.io/dynnomapp/) that enables accurate prediction of HER2 expression of metastasis based on primary tumor information (AUC=0.82). Among T-DXd-treated patients, a higher response rate was observed in cohort 1 (ORR=65.8%) and cohort 3 (ORR=72.2%) compared to cohort 2 (ORR=37.0%). Additionally, cohort 1 (median PFS=17.0 months, median OS=34.1 months) and cohort 3 (median PFS=17.2 months, median OS not reached) exhibited superior PFS and OS compared to cohort 2 (median PFS=7.7 months, median OS=18.5 months).

Conclusions

The HER2 expression in metastatic specimen is more accurate in predicting the efficacy of T-DXd compared to primary specimen. Therefore, re-evaluation of HER2 status in metastatic lesions is recommended to make informed T-DXd treatment decisions in advanced breast cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Sun Yat-sen University Cancer Center.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.