Molecular landscape and prognostic value of HER2 low-expression on metastatic colorectal cancer.

229 Background: HER2 dual blockade showed the promise in clinical trials in patients (pts) with HER2-positive (HER2-Pos) metastatic colorectal cancer (mCRC). A phase I/II study of a novel anti-HER2 antibody-drug conjugate (HER2-ADC) showed promising activities across different cancer subtypes including HER2-Pos mCRC, and also showed a hint of activity for low-expressing (HER2-L) mCRC, regardless of RAS mutation. However, molecular landscape and prognostic value of HER2-L on mCRC are unclear. Methods: The eligibility included pts with mCRC who had undergone surgical resection of primary tumor. Using the specimen, HER2 expression was evaluated by immunohistochemistry (IHC) and FISH. Definition of HER2 positivity was as follows; HER2-Pos as IHC 3+ or IHC 2+/FISH positive: HER2-L as IHC 2+/FISH negative or IHC 1+: Negative (HER2-Neg) as IHC 0+. NGS tests were also done. Results: Between 2005 and 2015, a total of 370 pts were analyzed; 60% were male, with a median age of 64 y/o. Fifteen pts (4%) with HER2-Pos, 21 (6%) with HER2-L, and 334 (90%) with HER2-Neg were identified. Proportion of left-sided primary tumor was similar among groups ranging from 72% to 78%. No difference was observed in terms of major clinicopathological characteristics. The proportion of co-altered RAS mutations in HER2-L was significantly higher than HER2-Pos ( p = 0.037) and similar to HER2-Neg (27% in HER2-Pos vs. 62% in HER2-L vs. 56% in HER2-Neg). As of median follow-up of 24.8 months, median overall survival (mOS) in HER2-L was significantly better than that in HER2- Pos ( p = 0.029, 18.2 months in HER2-Pos vs. 33.3 in HER2-L vs. 27.9 in HER2-Neg). In 58 pts harboring RAS wild-type who received an anti-EGFR monoclonal antibody therapy, median progression-free survival (mPFS) in HER2-L tended to be better than that in HER2- Pos, with 2.2 months in HER2-Pos, 7.8 in HER2-L, and 5.5 in HER2-Neg ( p = 0.099). Conclusions: Since HER2-L mCRC had the high prevalence of co-altered RAS mutations but showed a better prognosis and might benefit more from an anti-EGFR therapy than HES2-Pos, the HER2-L mCRC seems to have a different biological behavior from HER2-Pos in terms of molecular landscape and prognostic value on mCRC.