Abstract CT172: A phase II trial of adjuvant PD-1 blockade with endocrine therapy in hormone receptor positive inflammatory breast cancer: Circulating biomarkers and molecular correlates of clinical outcomes

Abstract Patients with hormone receptor–positive (HR+) inflammatory breast cancer (IBC) who have residual disease after surgery represent a particularly high-risk group, yet current adjuvant treatment guidelines do not address their elevated recurrence rates compared with non-inflammatory breast cancers. In this single-center phase II study, 31 such patients (enrolled 2017–2021) received pembrolizumab every three weeks for up to 24 months combined with standard endocrine therapy. The median number of doses administered was 19, and 8 patients (26%) completed the full course of treatment. Two-year disease-free survival was 71% (95% CI, 57–89%), and median overall survival was not reached (median follow-up, 48 months). Seven patients (23%) experienced grade 3 adverse events, consistent with the known toxicity profile of pembrolizumab; no grade 4 events occurred. To investigate determinants of response, we performed exploratory analyses of longitudinal peripheral blood and paired surgical specimens. Ultrasensitive circulating tumor DNA (ctDNA) profiling showed that post-surgical ctDNA positivity was strongly prognostic and enabled molecular detection of relapse up to 15 months before clinical progression. An XGBoost classifier trained on peripheral immune profiles comprising 231 samples across multiple timepoints from 30 patients demonstrated moderate discriminatory performance for predicting progression (AUROC 0. 72), with declines in circulating CD3+ and terminally differentiated effector memory (TDEM) CD8+ T-cell frequencies emerging among the strongest features. Whole-exome sequencing of primary tumors and matched lymph node metastases from six patients revealed unique clonal expansions in metastatic sites. Two patients (33%) remained disease-free and demonstrated lower variant allele frequencies in their lymph nodes compared to their primary disease sites, while four patients (67%) experienced disease recurrence and had an elevated mutational burden in their metastatic sites. Although no convergent clonal evolutionary pattern emerged, we found that copy-number alterations on chromosomes 11, 14, and 19 correlated with clinical outcomes. Notably, deletions involving immunoglobulin heavy chain loci (IGHD, IGHM) were identified in patients with prolonged disease control, suggesting a potential contribution of B-cell–associated immunity in favorably shaping the tumor immune microenvironment. Other lymph node-specific genetic deletions (HCN2, CD177P1, TEX101) were also found to be shared exclusively in patients with durable responses, indicating a favorable role in disease biology and warranting further experimental validation. This study represents the first evaluation of adjuvant PD-1 blockade in HR+ IBC and demonstrates encouraging clinical activity relative to historical expectations. The accompanying biomarker analyses offer initial insight into immune and genomic correlates of outcomes and may help identify patients most likely to benefit from immunotherapy in this aggressive subtype. Citation Format: Ranjan Upadhyay, Angela Alexander, Qing Ye, Ken Chen, John M. Elizarraras, Angela Marx, Megumi Kai, Clinton Yam, Hui Gao, Huiming Sun, Gregory J. Hogan, Siming Zhang, Matthew L. LaBella, Sarah Ratzel, Roland L. Bassett, MDACC Inflammatory Breast Cancer Team, Wendy A. Woodward, Bora Lim. A phase II trial of adjuvant PD-1 blockade with endocrine therapy in hormone receptor positive inflammatory breast cancer: Circulating biomarkers and molecular correlates of clinical outcomes abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT172.