59P - C8A, a potential predictive marker of trastuzmab benefit, is associated with immunological signatures in MSigDB

Date 07 May 2015
Event IMPAKT 2015
Session Welcome reception and Poster Walk
Topics Anti-Cancer Agents & Biologic Therapy
Breast Cancer
Cancer Immunology and Immunotherapy
Translational Research
Presenter Scooter Willis
Citation Annals of Oncology (2015) 26 (suppl_3): 15-24. 10.1093/annonc/mdv117
Authors S. Willis, B.M. Young, C. Williams, B. Leyland-Jones
  • Molecular And Experimental Medicine, Avera Cancer Institute, 57105 - Sioux Falls/US

Abstract

Body

An exploratory analysis of 20,464 genes, in 610 TransHERA FFPE samples revealed C8A, member of the membrane attack complex and part of the innate immune system, as a potential prognostic and predictive biomarker. Cox regression was used to model DFS where C8A as a categorical variable split on cohort mean has a treatment interaction (p < .001) indicating high expression of C8A benefited from trastuzmab (HR Trast/Obs = 0.23; 95% CI: 0.13-0.39; p < .001). A prognostic effect was also observed in the observation arm (HR high/low = 3.06; 95% CI: 1.86-5.03; p < 0.001) (SABCS Abst. P3-06-02). To identify possible phenotype differences in the DASL cohort between HER2+ tumors with high C8A expression compared to low C8A, Gene Set Enrichment Analysis was performed where enriched gene sets with a FDR adjusted p-value < .05 are statistically significant. Molecular Signature Database (MSigDB) gene sets tested, include immunologic signatures (n = 1910), canonical pathways (n = 1320), molecular GO terms (n = 1454), miRNA (n = 221), chromosome position (n = 326), transcription factors (n = 615), chemical genetic perturbations (n = 3402) and oncogenic signatures (n = 189). In the low C8A group, 741 of the 1910 gene sets (FDR < .05) had higher expression of mRNA for genes associated with immunologic response. The high C8A group had no statistically significant [R1] (p < .01) upregulated immunologic gene sets. No other gene sets with FDR < .05 were found in the collection of MSigDB gene sets tested. Preliminary results suggest that C8A is prognostic of DFS and predictive of trastuzumab benefit in the DASL cohort, but requires further validation. In addition, low expression of C8A indicates an enrichment of immunologic genes suggesting that high C8A mRNA is also a negative indicator of immune response. The Cancer Cell Line Encyclopedia data show that DMS454_LUNG, OV90_OVARY, and SNU719_STOMACH as examples that have high expression of C8A and a feature of those cancer cell lines as opposed to detecting an innate immune response. Molecular characterization of C8A high HER2+ tumors may indicate it is a new cancer phenotype that can escape immune response and become an important mechanism in cancer that impacts survival.

Disclosure: All authors have declared no conflicts of interest.