TY - JOUR
TI - Exploratory analysis of single-gene predictive biomarkers in HERA DASL cohort reveals that C8A mRNA expression is prognostic of outcome and predictive of benefit of trastuzumab
AU - Willis, S.
AU - Polydoropoulou, V.
AU - Sun, Y.
AU - Young, B.
AU - Tsourti, Z.
AU - Karlis, D.
AU - Long, B.
AU - Lin, X.
AU - Theel, S.
AU - Carlson, J.
AU - Györffy, B.
AU - Williams, C.
AU - Abramovitz, M.
AU - Dafni, U.
AU - Dowsett, M.
AU - Leyland-Jones, B.
JO - JCO Precision Oncology
PY - 2018
VL - null
TODO - 2
SP - 1-12
PB - American Society of Clinical Oncology
SN - null
TODO - 10.1200/PO.18.00016
TODO - complement component C8a;  messenger RNA;  trastuzumab, Article;  cancer prognosis;  cancer survival;  clinical outcome;  cohort analysis;  controlled study;  disease free survival;  gene expression;  human;  human epidermal growth factor receptor 2 positive breast cancer;  major clinical study;  phase 3 clinical trial (topic);  priority journal;  randomized controlled trial (topic);  stomach cancer
TODO - Purpose The Herceptin Adjuvant study is an international multicenter randomized trial that compared 1 or 2 years of trastuzumab given every 3 weeks with observation in women with human epidermal growth factor 2-positive (HER2+) breast cancer after chemotherapy. Identification of biomarkers predictive of a benefit from trastuzumab will minimize overtreatment and lower health care costs. Methods To identify possible single-gene biomarkers, an exploratory analysis of 3,669 gene probes not expected to be expressed in normal breast tissue was conducted. Disease-free survival (DFS) was used as the end point in a Cox regression model, with the interaction term between C8A mRNA and treatment as a categorical variable split on the cohort mean. Results A significant interaction between C8A mRNA and treatment was detected (P < .001), indicating a predictive response to trastuzumab treatment. For the C8A-low subgroup (mRNA expression lower than the cohort mean), no significant treatment benefit was observed (P = .73). In the C8A-high subgroup, patients receiving trastuzumab experienced a lower hazard of a DFS event by approximately 75% compared with those in the observation arm (hazard ratio [HR], 0.25; P < .001). A significant prognostic effect of C8A mRNA also was seen (P < .001) in the observation arm, where the C8A-high group hazard of a DFS event was three times the respective hazard of the C8A-low group (HR, 3.27; P < .001). C8A mRNA is highly prognostic in the Hungarian Academy of Science HER2+ gastric cancer cohort (HR, 1.72; P < .001). Conclusion C8A as a single-gene biomarker prognostic of DFS and predictive of a benefit from trastuzumab has the potential to improve the standard of care in HER2+ breast cancer if validated by additional studies. Understanding the advantage of overexpression of C8A related to the innate immune response can give insight into the mechanisms that drive cancer. © 2019 American Society of Clinical Oncology.
ER -