<i>HER2</i> Gene Expression Levels Are Predictive and Prognostic in Patients With Metastatic Colorectal Cancer Enrolled in CALGB/SWOG 80405.

Abstract

The phase III Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial found no difference in overall survival (OS) in patients with metastatic colorectal cancer receiving first-line chemotherapy in combination with either bevacizumab or cetuximab. We investigated the potential prognostic and predictive value of <i>HER2</i> amplification and gene expression using next-generation sequencing (NGS) and NanoString data. Primary tumor DNA from 559 patients was profiled for <i>HER2</i> amplification by NGS (FoundationOne CDx). Tumor tissue from 925 patients was tested for NanoString gene expression using an 800-gene panel. OS and progression-free survival (PFS) were the time-to-event end points. High <i>HER2</i> expression (dichotomized at median) was associated with longer PFS (11.6 <i>v</i> 10 months, <i>P</i> = .012) and OS (32 <i>v</i> 25.3 months, <i>P</i> = .033), independent of treatment. An OS benefit for cetuximab versus bevacizumab was observed in the high <i>HER2</i> expression group (<i>P</i> = .02), whereas a worse PFS for cetuximab was seen in the low-expression group (<i>P</i> = .019). When modeled as a continuous variable, increased <i>HER2</i> expression was associated with longer OS (hazard ratio [HR], 0.83 [95% CI, 0.75 to 0.93]; adjusted <i>P</i> = .0007) and PFS (HR, 0.82 [95% CI, 0.74 to 0.91]; adjusted <i>P</i> = .0002), reaching a plateau effect after the median. In patients with <i>HER2</i> expression lower than median, treatment with cetuximab was associated with worse PFS (HR, 1.38 [95% CI, 1.12 to 1.71]; adjusted <i>P</i> = .0027) and OS (HR, 1.28 [95% CI, 1.02 to 1.59]; adjusted <i>P</i> = .03) compared with that with bevacizumab. A significant interaction between <i>HER2</i> expression and the treatment arm was observed for OS (<i>P</i>_<i>intx</i> = .017), PFS (<i>P</i>_<i>intx</i> = .048), and objective response rate (<i>P</i>_<i>intx</i> = .001). <i>HER2</i> gene expression was prognostic and predictive in CALGB/SWOG 80405. <i>HER2</i> tumor expression may inform treatment selection for patients with low <i>HER2</i> favoring bevacizumab- versus cetuximab-based therapies.