Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.
—Edith A. Perez, MD, and colleagues
In a study reported in the Journal of Clinical Oncology, Edith A. Perez, MD, of the Mayo Clinic, Jacksonville, and colleagues found that an immune function gene profile was associated with significantly improved relapse-free survival among patients with early-stage HER2-positive breast cancer who had trastuzumab (Herceptin) added to adjuvant chemotherapy in the North Central Cancer Treatment Group (NCCTG) N9831 trial.1
Whole transcriptome analysis using cDNA-mediated annealing, selection, extension, and ligation (DASL) technology was performed on 1,282 samples from NCCTG N9831. Cox proportional hazard ratios (HRs) adjusted for significant clinicopathologic risk factors were used to determine the association of each gene with relapse-free survival in 433 patients who received chemotherapy (paclitaxel) alone and 849 patients in two study groups who also received trastuzumab (concurrent with or after paclitaxel). Network and pathway analyses were used to identify key biologic processes linked to relapse-free survival, and the final gene signature was built using a voting scheme.
Immune Function Genes
In pathway analyses, integrin signaling, Alzheimer disease-presenilin pathway, and G to M cell-cycle transition pathways were the most significant pathways associated with reduced relapse-free survival among patients receiving trastuzumab. The most significant pathways associated with increased relapse-free survival in these patients were cytokine-cytokine receptor interaction, T-cell–receptor signaling in CD8-positive T cells, interferon gamma pathway, tumor necrosis factor–receptor signaling pathway, cell-surface interaction at the vascular endothelium, and class I PI3K signaling events. The fact that four of six significant pathways are involved in immunologic functions strongly suggested an association between immune response and increased relapse-free survival with trastuzumab in HER2-positive disease.
Similarly, 10 of 13 Gene Ontology biologic process terms for genes with a significant hazard ratio for relapse-free survival that were enriched among trastuzumab patients were for immune functions, including T-cell and B-cell responses, chemokine signaling and chemotaxis, and inflammation. Among 87 immune function genes defined by the 10 immune function Gene Ontology terms, 14 exhibiting a significant probe by treatment group interaction were included in the final profile (AFAP1L2, AMICA1, CCL21, CCR4, CD1E, CD40LG, CXCL12, FYN, HLA-DOB, IGFBP4, IRF8, PTGDR, PTGER4, and TLR10).
A model was developed that defined immune gene enrichment based on expression of any 9 or more of the 14 immune function genes at or above the 0.40 quantile for the population. Compared with patients with enriched tumors in the chemotherapy group, relapse-free survival was significantly prolonged among trastuzumab patients with enriched tumors (HR = 0.35, 95% confidence interval [CI] = 0.22–0.55, P < .001) but not among chemotherapy patients with nonenriched tumors (HR = 0.9, 95% CI = 0.6–1.37, P = .64) or trastuzumab patients with nonenriched tumors (HR = 0.89, 95% CI = 0.62–1.28, P = .53).
On multivariate analysis, which showed a significant interaction of immune-enrichment status and treatment group (P < .001), relapse-free survival was significantly prolonged for trastuzumab patients with enriched tumors vs chemotherapy patients with enriched tumors (HR = 0.36, 95% CI = 0.23–0.56, P < .001). There was no difference observed between trastuzumab patients and chemotherapy patients with nonenriched tumors (HR = 0.98, 95% CI = 0.68–1.41, P = .91).
“Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab,” concluded the investigators.
They observed: “The potential clinical significance of our results, within the context of identification of patients who are likely to benefit (increased [relapse-free survival]) from adjuvant trastuzumab, is considerable. Identification of patients who are unlikely to benefit from trastuzumab on the basis of evaluation of the immune status of the tumor before initiation of therapy may have even greater significance. Patients with low immune function gene expression scores might be enrolled onto trials to test the efficacy of HER2-targeted regimens that combine trastuzumab with some other therapeutic agent. Alternatively, these patients might be the focus of future clinical trials designed to evaluate therapeutic approaches that might enhance the immune activity within HER2-positive tumors and thereby sensitize the tumors to biologic therapies.”
One strategy in this regard cited by the investigators is the inhibition of immunosuppressive signaling pathways—eg, with agents targeting PD-1 (programmed cell death protein 1) or its ligand PD-L1. Another strategy is to increase immunoreactivity via modification of the immunoglobulin backbone of anti-HER2 antibodies. ■
Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.
1. Perez EA, Thompson EA, Ballman KV, et al: Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial. J Clin Oncol 33:701-708, 2015.
See commentary by Randy F. Sweis, MD, and Olufunmilayo I. Olopade, MD.
The addition of trastuzumab (Herceptin) to adjuvant chemotherapy undoubtedly transformed HER2-positive breast cancer from one of the most deadly subtypes to a highly treatable disease. Randomized phase III trials established adjuvant trastuzumab as standard of care in HER2-positive breast...