Abstract PO2-04-01: Predictors of exceptional response to first line HER2-targeted therapy for metastatic breast cancer
Authors: Morganti Stefania , Li Tianyu , Santos Katheryn , Hughes Melissa , Priedigkeit Nolan , Li Yvonne , Lipsyc-Sharf Marla , Kirkner Gregory , Files Janet , Kasparian Julie , Grant Elizabeth , Gupta Gunjan , Curigliano Giuseppe , Tolaney Sara , Cherniack Andrew , Tayob Nabihah , Lin Nancy , Parsons Heather 
Published: May 2024

Abstract
Background
HER2-targeted therapies have transformed the trajectory of HER2-positive (HER2+) metastatic breast cancer (MBC), with a subgroup of responders remaining on first line (1L) therapy for many years (yrs). Despite these promising outcomes, the paradigm remains palliative, with some patients (pts) receiving therapy indefinitely. Opportunities to interrupt therapy are controversial and anecdotal in the setting of a limited understanding of long-term responders and lack of predictive biomarkers.
Methods
We identified prevalent pts with HER2+ MBC seen and consented at Dana-Farber Cancer Institute between 2010 and 2023, regardless of the original date of MBC diagnosis. Exceptional responders (ExRes) were pts without evidence of progressive disease (PD) 3 yrs from initiation of 1L therapy for MBC. Conventional responders (ConRes) were pts who experienced PD within 3 yrs of 1L treatment initiation. We compared clinicopathological characteristics and treatment patterns between ExRes and ConRes using Chi-square or Wilcoxon test. We analyzed median time to treatment switch due to PD (TTS-PD) – i.e., time from metastatic diagnosis to 1L treatment end due to PD - and overall survival, via the Kaplan-Meier method and with a landmark analysis at year 3 (Y3). Our primary aim was to identify predictors of exceptional response to 1L anti-HER2 therapy.
Results
Of 635 pts with HER2+ MBC, we identified 147 ExRes and 370 ConRes and excluded 118 pts due to follow up ≤ 3 yrs and no PD events. Median follow up was 7.1 yrs (IQR 5.5-11.0) for ExRes and 7.1 yrs (IQR 4.0-11.4) for ConRes. Median age at MBC diagnosis was 50.7 yrs (range 21.9-91.9) for ExRes and 49.8 yrs (26.9-82.3) for ConRes. ExRes presented more often with de novo MBC than ConRes (52.1 vs 30.6%, p&lt; 0.0001). On metastatic samples, more ExRes than ConRes had HER2 3+ tumors by immunohistochemistry (IHC) (93.7 vs 81.0%, p=0.002), whereas the proportion of ER-positive disease was similar between the two groups (45.6 vs 53.4%, p=0.1). Most pts received (neo)adjuvant anti-HER2 agents in both groups (62.5 vs 72.7%, p=0.1). More ExRes than ConRes (55.8 vs 42.7% p=0.007) received 1L chemotherapy (CT) plus trastuzumab (H)/pertuzumab (P). Alternative 1L treatments were CT plus H (26.5 vs 25.7%), H +/- P +/- endocrine therapy (8.2 vs 10.5%), T-DM1 (2 vs 9.2%), tyrosine kinase inhibitors-based regimens (7.5 vs 10.8%). For pts with recurrent MBC, disease-free interval was longer for ExRes than ConRes (median 4.7 vs 3.4 yrs, p=0.01). Visceral involvement at MBC relapse was similar for ExRes and ConRes (78.2 vs 77.8%, p=0.9). Brain metastases at any timepoint were less frequent among ExRes than ConRes (42.9 vs 55.1%, p=0.01).
Among ExRes, 70 (47.6%) pts experienced PD after Y3, with a median TTS-PD of 4.6 (4.1-5.1) yrs. In a landmark analysis at Y3, the 2-year TTS-PD was 68.5% (95% CI: 59.8%-75.7%) (5 yrs from treatment start), and 4-year overall survival was 86.5% (95% CI: 78.1%-91.9%) (7 yrs from treatment start). ConRes received a median of 5 (1-19) treatment regimens for MBC, with a median 1L TTS-PD of 12 (10.8-13) mo. A total of 89 (60.5%) ExRes and 214 (57.8%) ConRes underwent tumor sequencing. Data comparing genomic features between ExRes and ConRes will be presented.
Conclusions
In this prospective cohort, 28% of pts with HER2+ MBC had exceptional response to 1L anti-HER2 therapy. Consistent with prior data, ExRes present more frequently with de novo disease and HER2 IHC 3+ tumors. In our cohort, ExRes had a median follow-up of 7.1 years and 52.4% never experienced PD. Although a significant proportion of pts with HER2+ MBC derive long-term benefit from anti-HER2 therapy, the treatment paradigm remains palliative, and it is unknown whether biomarkers may reliably predict exceptional response and guide future treatment. Ongoing work will explore whether genomic features vary between ExRes and ConRes.
Citation Format: Stefania Morganti, Tianyu Li, Katheryn Santos, Melissa Hughes, Nolan Priedigkeit, Yvonne Li, Marla Lipsyc-Sharf, Gregory Kirkner, Janet Files, Julie Kasparian, Elizabeth Grant, Gunjan Gupta, Giuseppe Curigliano, Sara Tolaney, Andrew Cherniack, Nabihah Tayob, Nancy Lin, Heather Parsons. Predictors of exceptional response to first line HER2-targeted therapy for metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-01.