Summary:

Genomic Analysis Reveals That Immune Function Genes Are Strongly Linked to Clinical Outcomes in the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial

Authors: Edith A. Perez, E. Aubrey Thompson, Karla V. Ballman, S. Keith Anderson, Yan W. Asmann, Krishna R. Kalari, Jeanette E. Eckel-Passow, Amylou C. Dueck, Kathleen S. Tenner, Jin Jen, Jian-Bing Fan, Xochiquetzal J. Geiger, Ann E. McCullough, Beiyun Chen, Robert B. Jenkins, George W. Sledge, Eric P. Winer, Julie R. Gralow, and Monica M. Reinholz

Source: J Clin Oncol 33:701-708, 2015. Genomic analysis reveals that immune function genes are …

It has been demonstrated that adjuvant treatment with trastuzumab has been effective in the treatment of early-stage HER-2 positive breast cancer. Despite this targeted therapy, 20-25% of patients develop tumor relapse. This raises the need to identify genomic and/or biologic features related to this relapse.

Perez et al. analyzed whole transcriptomes of 1,282 samples from patients with HER-2 positive breast tumors in the North Central Cancer Treatment Group N9831 (NCCTG-N9831) adjuvant trastuzumab trial. The group subsequently completed the first demonstration of a cohort of immune function genes that may predict which patients with HER-2 positive breast tumors may benefit from trastuzumab adjuvant treatment. Four hundred and eighty-five genes were significantly associated with relapse-free survival (RFS) in patients treated with trastuzumab. The most significant pathways found to be associated with decreased RFS include integrin signaling, Alzheimer disease-presenilin pathway, and G to M cell cycle transition pathway. Prolonged RFS after adjuvant trastuzumab treatment was associated with T cell receptor signaling in CD8+ T cells, interferon gamma pathway, tumor necrosis factor receptor signaling pathway, cell surface interaction at the vascular endothelium and class I PI3K signaling event pathways.

Because most of the relevant pathways are associated with immune function, there is a strong correlation between immune response and prolonged RFS in patients with HER-2 positive tumors treated with adjuvant trastuzumab. Fourteen immune function genes were identified as predictively associated with prolonged RFS. If a tumor expressed 9 or more of these genes, the tumor was designated as immune response enriched (IRE). These patients with IRE tumors were found to exhibit significantly increased RFS after adjuvant trastuzumab, compared to just chemotherapy alone.

In summary, the data presented by Perez et al. suggest an immunologic component to relapse-free survival in patients with HER-2 positive breast tumors given adjuvant trastuzumab therapy. Tumors positive for certain immune function genes show positive correlation with RFS after adjuvant trastuzumab therapy. The clinical significance of these findings is that patients that express these immune response genes in the tumor microenvironment will be identified as benefitting most from adjuvant trastuzumab therapy. Patients with low expression of these IRE genes may be offered other immune-based therapies, such as vaccinations, check point inhibitors or adoptive T cell therapy to drive immune responses to make trastuzumab therapy more effective.