HERA is an international multi-center randomized trial comparing 1 or 2 years trastuzumab, given every 3 weeks, with observation in women with HER2+ breast cancer after standard neoadjuvant or adjuvant chemotherapy. From December 2001 to June 2005, 5102 patients were randomized. Comparing 1 year trastuzumab with observation at 8 years of follow-up, statistically significant differences in disease-free survival (DFS) and overall survival, despite crossover to trastuzumab of observation arm patients, were found. No benefit in DFS of 2 years compared to 1 year trastuzumab was found[Goldhirsch 2013].
To determine possible predictive single-gene biomarkers, an exploratory ITT analysis, with DFS as the primary endpoint, was conducted using mRNA expression data from 610 TransHERA FFPE samplesprofiled on Illumina Whole-Genome DASL cubic spline normalization was applied to the data. Outcome was obtained from the HERA database with 8 years median follow-up and clinical cut-off date April 12, 2012. Characteristics were well balanced between treatment groups. The exploratory analysis of 20,464 genes using DFS as the endpoint identified C8A as a possible biomarker that is prognostic and predictive of response to treatment. Cox regression was used to model DFS, with the interaction term between treatment and C8A as a continuous and a categorical variable split on the cohort mean. The observation arm consists of 199 samples with 66 events and the trastuzumab arm(1&2-year combined) of 411 samples with 108 events.
A statistically significant interaction between C8A mRNA and treatment was detected (p<0.001), indicating that C8A mRNA is predictive of response to trastuzumab treatment. For the C8A low subgroup (mRNA expression lower than the cohort mean) no significant treatment benefit is observed (p=0.73). On the other hand for the C8A high subgroup, patients in the trastuzumab arm experience a lower hazard of a DFS event by almost 75% compared to patients from the observation arm (HR=0.25; 95%CI:0.15-0.43, p<0.001). A significant prognostic effect of C8A mRNA is also observed (p<0.001) in the observation arm, where for the C8A high group the hazard of a DFS event is three times the respective hazard of the C8A low group (HR-=3.27; 95%CI:2.01-5.32, p<0.001).
C8A is a member of the membrane attack complex and is part of the innate immune system. C8A inserts into the membrane of the target cell and binds with multiple copies of the pore-forming C9 leading to cell lysis. From the GeneAtlas, C8A is highly expressed in liver tissue suggesting an advantage for tumors with high expression of C8A and innate immune response. The Cancer Cell Line Encyclopedia indicates a wide range of C8A mRNA expression.
C8A as a single gene biomarker that is prognostic of DFS and predictive of benefit from trastuzumab has the potential to improve the standard of care in HER2+ breast cancer. Understanding the advantage of over expression of C8A related to the innate immune response can give insight into the mechanisms that drive cancer. We note with caution that this finding is the result of an exploratory analysis and is being pursued in additional trastuzumab cohorts for further validation.
Citation Format: Scooter Willis, Varvara Polydoropoulou, Zoi Tsourti, Urania Dafni, Brandon Young, Bradley Long, Pradip De, Nandini Dey, Casey Williams, Mitch Dowsett, Brian Leyland-Jones. Exploratory analysis of single gene predictive biomarkers in TransHERA DASL cohort reveals that C8A mRNA expression is prognostic of outcome and predictive of benefit of trastuzumab [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-02.