Background: Metastatic breast cancer (MBC) remains a significant clinical challenge. Fam-trastuzumab deruxtecan-nxki(T-DXd) has demonstrated notable efficacy in clinical trials such as DESTINY-Breast01 and DESTINY-Breast09. T-DXd has shown promising results in treating not only HER2-positive but also HER2-low and HER2-ultralow subtypes. However it is still unclear how HER2 status and its changes over time affect treatment outcomes with T-DXd. Moreover, there is emerging evidence that HER2 status can change during or after T-Dxd treatment. This study uses real-world data (RWD) from a large, clinically annotated cohort to evaluate the impact of HER2 status and its dynamics on treatment outcome with T-DXd as well as T-DXd treatment on HER2 status.

Methods: A retrospective analysis was conducted using RWD from 300 MBC patients treated with T-DXd, sourced from the Tempus database1. Key endpoints included real-world best overall response (rwBOR; non-responder vs. responder), real-world progression free survival (rwPFS), real-world time to next treatment (rwTTNT), and real-world overall survival (rwOS). Patient outcomes were curated by Tempus based on the physician assessment. Patients with complete response (CR) or partial response (PR) were classified as responders while those with stable disease (SD) or progressive disease (PD) were classified as non-responders. HER2 status was defined using immunohistochemistry (IHC; 0, 1+, 2+, 3+) and in-situ hybridization (ISH; negative, positive). HER2 low was defined as IHC 1+ or IHC 2+ with a negative ISH, HER2 positive was defined as IHC 2+ with a positive ISH or IHC 3+. HER2 status change was assessed in patients with both pre- and post-T-DXd HER2 status data, with post-treatment IHC conducted at least six weeks after treatment initiation. Patients with multiple pre-T-DXd treatment measurements showing no change in HER2 status over time were considered HER2 IHC Stable. Logistic regression was used for rwBOR, and Cox proportional hazards models with log-rank tests were applied for rwPFS, rwTTNT, and rwOS while adjusting for age at T-DXd treatment, ER/PR status, care plan, sampling time, tissue location.

Results: Among 300 patients, 298 subjects had HER2 data, 223 subjects had pre-T-DXd HER2 IHC Stability data. Compared to HER2-positive, HER2-low patients had significantly worse outcomes: rwBOR (OR=1.87, p=0.035), rwPFS (HR=1.60, p=2.32X10-3), rwTTNT (HR=1.75, p=4.30X10-3), and rwOS (HR=2.35, p=2.02X10-4). Patients with stable HER2 IHC status had more favorable outcomes: rwBOR (OR=0.27, p=1.23X10-4), rwPFS (HR=0.58, p=0.0014), rwTTNT (HR=0.61, p=0.025), and rwOS (HR=0.48, p=2.98X10-3). Among 62 out of 67 patients with pre- and post-treatment HER2-status available, all were classified as either HER2-positive or HER2-low before receiving T-DXd treatment. Following treatment, 21 (34%) of these 62 patients exhibited a change in HER2 status with T-DXd treatment. Specifically, among 31 HER2-positive patients, 5 (16%) dropped to HER2-negative and 7 (22%) to HER2-low and among 31 HER2-low patients, 9 (29%) dropped to HER2-negative. A change in HER2 status post-T-DXd treatment was associated with increased risk for progression (rwPFS HR=1.89, p=0.041). However, due to the relatively small sample size of 67, these findings should be interpreted with caution.

Conclusions: This study highlights the clinical relevance of monitoring HER2 status and the dynamics of HER2 status and its impact on treatment outcome with a HER2-targeting ADC, T-DXd in MBC. Changes in HER2 status post-treatment with T-DXd were associated with poorer progression-free survival, underscoring the importance of ongoing HER2 monitoring. These real-world insights can inform personalized treatment strategies for MBC.

References: 1. www.tempus.com

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