Characteristics of Exceptional Responders to First-Line HER2-Targeted Therapy for HER2+ MBC

There is limited understanding of the clinical characteristics of long-term responders to HER2-targeted therapies in HER2+ metastatic breast cancer (MBC) and lack of predictive biomarkers. The current study was undertaken to characterize long-term responders and identify predictors of exceptional response to first-line anti-HER2 therapy.

This study included patients with HER2+ MBC treated at Dana-Farber Cancer Institute between 2010 and 2023, regardless of the original date of MBC diagnosis. Responders were classified as exceptional responders (ExRes; defined as patients without evidence of progressive disease [PD] 3 years from first-line MBC therapy initiation) or conventional responders (ConRes; defined as patients who experienced PD within 3 years of first-line treatment initiation). Clinicopathological characteristics and treatment patterns between the 2 cohorts were compared; median time to treatment switch due to PD (TTS-PD; defined as time from metastatic diagnosis to first-line treatment end due to PD) was analyzed using the Kaplan-Meier method, and overall survival (OS) was analyzed using a landmark analysis at year 3.

A total of 635 patients with HER2+ MBC were included in the analysis. Of the evaluable patients, 147 were classified as ExRes and 370 as ConRes. Median follow-up was 7.1 years for both cohorts, and median age at MBC diagnosis was similar (ExRes: 46.8 years; ConRes: 46.5 years). A significantly higher proportion of patients in the ExRes cohort presented with de novo MBC compared with the ConRes cohort (52.1% vs 30.6%; P<.0002). In the metastatic samples, a significantly higher percentage of patients in the ExRes cohort had HER2 3+ tumors by immunohistochemistry (IHC) versus the ConRes cohort (93.7% vs 81.0%; P=.002), while there was no between-group difference in the proportion of ER-positive disease (45.6% vs 53.4%).

A significantly higher proportion of patients in the ExRes cohort received first-line chemotherapy plus trastuzumab/pertuzumab compared with the ConRes cohort (55.8% vs 42.7%; P=.007). Among patients with recurrent MBC, disease-free interval was significantly longer in the ExRes cohort versus the ConRes cohort (median, 4.7 vs 3.4 years; P=.01); visceral involvement at MBC relapse was similar in both groups. At any timepoint, the proportion of patients with brain metastases was significantly lower in the ExRes cohort compared with the ConRes cohort (42.9% vs 55.1%; P=.01).

In the ExRes cohort, the majority of patients did not experience progressive disease after year 3; median TTS-PD was 4.6 years, and 2-year TTS-PD was 68.5% (5 years from treatment start). In a landmark analysis at year 3, 4-year OS was 86.5% (7 years from treatment start). In the ConRes cohort, the median first-line TTS-PD was 12 months; patients received a median of 5 treatment regimens for MBC.

Most patients in both cohorts underwent tumor sequencing (ExRes: 85/147; ConRes: 206/370). Higher prevalence of MYC (19% vs. 5%) and PIK3CA (37% vs. 21%) alterations was reported in the ConRes cohort, implicating these alterations in development of resistance mechanisms to anti-HER2 therapy.

In this prospective HER2+ MBC cohort, one-third of patients with HER2+ MBC achieved exceptional response to first-line HER2-targeted therapy, and presented more frequently with de novo disease and HER2 IHC 3+ tumors.

Source:

Morganti S, Li T, Santos K, et al. Predictors of exceptional response to first line HER2-targeted therapy for metastatic breast cancer. Presented at the 46th San Antonio Breast Cancer Symposium Annual Meeting, December 5-9, 2023; San Antonio, TX: Abstract PO2-04-01.