Introduction Immune checkpoint inhibitor (ICI) therapy is efficacious for many tumor types and has been approved in both early-stage and metastatic triple negative breast cancer. However, no such approval exists for hormone receptor positive (HR+) breast cancer (BC) which typically has a lower TMB, lower PD-L1 expression, and lower numbers of tumor infiltrating lymphocytes, leaving an unmet need for a biomarker to determine ICI response. The 27-gene IO score has previously demonstrated association with response to ICI therapy in NSCLC, mUC, and TNBC but has not yet tested a cohort of HR+/HER2- breast cancer.
Methods To determine the ability of the IO score to identify responders with HR+/HER- BC clinical and expression data from publicly available RNA expression data from the I-SPY2 trial were retrieved from Gene Expression Omnibus (GEO) under accession number GSE194040. Expression data were normalized, combined, batch corrected, and log-transformed by the submitting institution. This left an expression matrix of 19134 genes and 988 samples for analysis as well as corresponding clinical data. Within this sample set, 40 patients were HR+/HER- and received pembrolizumab and cytotoxic chemotherapy while 64 patients comprised the control arm (chemotherapy only).
Results In the I-SPY2 trial, within the 40 patients who received pembrolizumab, 12 patients achieved pCR (30%) and 19 patients were IO+ (47.5%). Of the 12 pCR patients, 9 were IO+ (75%) and of the 28 RD patients, 18 were IO- (64%), resulting in an odds ratio of 5.4 (95% CI 1.2-24.7, p< 0.03). Considering the 64 HR+/HER- patients in the paclitaxel arm, 10 achieved pCR (15.6%) and 21 were IO+ (32.8%). Of the 10 pCR patients, 5 were IO+ (50%) and of the 54 RD patients, 38 were IO- (70%), resulting in an odds ratio of 2.4 (95% CI 0.6-9.3, p>0.2).
Conclusions Despite a generally low inflammatory tumor microenvironment characteristic of the HR+ BC phenotype, the IO+ group was 3x more likely to achieve pCR with the addition of pembrolizumab to chemotherapy. These data extend on previous findings in neoadjuvant treatment of TNBC and advanced colon cancer that IO score is associated with response only in the presence of ICI therapy, not in the presence of chemotherapy alone. This is the first study to demonstrate the association of IO score with pathologic complete response to immune therapy in hormone receptor positive BC.
Citation Format: Robert S. Seitz, Tyler J. Nielsen, Brian Ring, Catherine T. Cronister, Matthew G. Varga, Daniel Bailey, Matteo Dugo, Giampaolo Bianchini, Douglas T. Ross. The 27-gene IO score is associated with pathologic complete response (pCR) in HR+/HER2- breast cancer patients treated with pembrolizumab in the I-SPY2 Trial. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-26.