Immune Function Genes Strongly Linked to Outcome of Trastuzumab Trial
•Immune function gene expression was analyzed in 1282 samples from patients with human epidermal growth factor receptor 2–positive breast cancer who were enrolled in the adjuvant trastuzumab trial, the North Central Cancer Treatment Group N9831. Patients who exhibited enrichment in immune gene expression had greater relapse-free survival with trastuzumab treatment than patients who did not express high levels of the immune genes.
•Elevated immune function gene expression may indicate a predictive advantage for trastuzumab treatment in some patients.
To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2-positive breast cancer.
PATIENTS AND METHODS
DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme.
Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene-enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P < .001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P = .53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P = .64).
Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.