Abstract PS2-07-12: Gut microbiome composition predicts pathologic complete response in patients with early-stage HER2-positive breast cancer receiving neoadjuvant HER2-targeted therapy +/- immunotherapy with pembrolizumab

Abstract Background: The gut microbiome has been shown to influence response to immune checkpoint inhibitors (ICI). This study aimed to investigate the association between gut microbiome profiles and clinical outcomes in patients with early-stage HER2-positive (HER2+) breast cancer receiving neoadjuvant HER2-targeted therapy +/- immunotherapy with pembrolizumab (K) as part of the randomized phase II neoHIP trial. Methods: Patients with stage II-III HER2+ breast cancer were randomized to 3 treatment arms: Arm A consisted of paclitaxel (T), trastuzumab (H), and pertuzumab (P), THP; Arm B of THP-K; and Arm C of TH-K. Fecal samples were collected at baseline, cycle 3 day 1, surgery, and at 30 and 60 days post-surgery and were analyzed using deep shotgun metagenomics sequencing. Pre-operative fecal samples were analyzed according to pathologic complete response (pCR) and onset of diarrhea during the neoadjuvant period. Comparisons were adjusted to control for false discovery rates (q-value). Results: 99 fecal samples (Arm A: n=32; Arm B: n=48; Arm C: n=19) from 27 patients were included in the analysis. Bacterial diversity by Jaccard analysis was significantly different across all time points for all arms (all p<0.05; q<0.05). In the THP and THP-K arms, Jaccard analysis demonstrated differences in gut microbiome diversity in patients who achieved pCR versus non-pCR (p=0.009; q=0.009). In patients treated with THP who achieved pCR, multiple species were in greater abundance including GGB9237 SGB14179 (log fold change [LFC] 6.87), GGB34797 SGB14322 (LFC 6.25), and Faecalicatena fissicatena (LFC 4.61) compared to those with non-pCR (all p<1E-5; q<0.01). In the THP-K arm, patients who achieved pCR had different species in greater abundance, including GGB9365 SGB14341 (LFC 3.15), Hydrogenoanaerobacterium saccharovorans (LFC 2.92), and GGB9502 SGB14899 (LFC 2.56) compared to those with non-pCR (all p<0.0001; q<0.01). Comparing those who achieved pCR in THP vs. THP-K, GGB9715 SGB15260 (LFC 4.89), Brotolimicola acetigignens (LFC 4.88), and Clostridiaceae bacterium Marseille Q4149 (LFC 4.54) were higher in abundance in the THP-K arm, and GGB34797 SGB14322 (LFC 6.27) and GGB3175 SGB4191 (LFC 5.73) were depleted in the THP-K arm (all p<0.0001; q<0.05). In patients with diarrhea vs. without diarrhea, beta diversity was significantly different in the THP arm by Bray Curtis analysis (p<0.05; q<0.05) and in the THP-K arm by Jaccard analysis (p<0.05; q<0.05), with multiple species in different abundances in those with and without diarrhea in both arms (p<0.05). Conclusion: This is the first study to demonstrate that the pre-operative gut microbiome influences response to ICI in patients with early-stage HER2+ breast cancer. Patients who achieved pCR had a significantly different microbiome profile compared to those with residual disease. This study highlights the role of the gut microbiome in influencing response to ICI in patients with breast cancer treated in the curative intent setting. Citation Format: A. LeVee, K. Lee, S. Rice, I. Chan, S. Sridharan, S. Shiao, S. Pal, H. McArthur. Gut microbiome composition predicts pathologic complete response in patients with early-stage HER2-positive breast cancer receiving neoadjuvant HER2-targeted therapy +/- immunotherapy with pembrolizumab [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-07-12.